Soluble guanylate cyclase stimulators

ABSTRACT

The invention provides compounds of the Formula (I) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salts thereof, wherein X, Y, Z, R 1 , R 2 , R 4 , R a , and the subscripts m, p, and q are as described herein. The compounds or their pharmaceutically acceptable salts can modulate the body&#39;s production of cyclic guanosine monophosphate (“cGMP”), and are generally suitable for the therapy and prophylaxis of diseases which are associated with a disturbed cGMP balance. The invention also provides pharmaceutical compositions which comprise compounds of Formula (I) or pharmaceutically acceptable salts thereof. The invention also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of the abovementioned diseases and for preparing pharmaceuticals for this purpose.

BACKGROUND OF THE INVENTION

Cyclic GMP (cGMP) is an important intracellular messenger which triggersa multitude of different effects via the modulation of cGMP-dependentprotein kinases, phosphodiesterases and ion channels. Examples are therelaxation of smooth muscles, the inhibition of thrombocyte activationand the inhibition of the proliferation of smooth-muscle cells and ofleukocyte adhesion. cGMP is produced by particulate and solubleguanylate cyclases as a response to a number of extracellular andintracellular stimuli. In the case of the particulate guanylatecyclases, stimulation is essentially effected by peptidic messengers,such as the atrial natriuretic peptide or the cerebral natriureticpeptide. The soluble guanylate cyclases (“sGC”), which are cytosolicheterodimeric heme proteins, in contrast, are essentially regulated by afamily of low-molecular-weight factors which are formed enzymatically.The most important stimulant is nitrogen monoxide (“NO”) or a closelyrelated species. The function of other factors such as carbon monoxideor the hydroxyl radical is still largely unclear. The binding of NO tothe heme with formation of a penta-coordinate heme-nitrosyl complex isproposed as the mechanism of the activation by NO. The associatedrelease of the histidine which is bound in the basal state to the ironconverts the enzyme into the active conformation.

Active soluble guanylate cyclases are each composed of an α and a βsubunit. Several subunit subtypes have been described which differ fromone another with respect to sequence, tissue-specific distribution andexpression in different development stages. The subtypes al and β₁ aremainly expressed in brain and lung, while β₂ is found in particular inliver and kidney. The subtype α₂ was shown to be present in human fetalbrain. The subunits referred to as α₃ and β₃ were isolated from humanbrain and are homologous to α₁ and β₁. More recent works indicate anα_(2i) subunit which contains an insert in the catalytic domain. Allsubunits show great homologies in the region of the catalytic domain.The enzymes presumably contain one heme per heterodimer, which is boundvia β₁-Cys-78 and/or β₁-His-105 and is part of the regulatory center.

Under pathologic conditions, the formation ofguanylate-cyclase-activating factors can be reduced, or theirdegradation may be promoted owing to the increased occurrence of freeradicals. The resulting reduced activation of the sGC leads, via aweakening of the respective cGMP-mediated cellular response, for exampleto an increase of the blood pressure, to platelet activation or toincreased cell proliferation and cell adhesion. As a consequence,formation of endothelial dysfunction, atherosclerosis, hypertension,stable or unstable angina pectoris, thrombosis, myocardial infarction,strokes or erectile dysfunction results. Pharmacological stimulation ofsGC offers a possibility to normalize cGMP production and therefore maymake possible the treatment and/or prevention of such disorders.

For the pharmacological stimulation of the sGC, use has been made ofcompounds whose activity is based on an intermediate NO release, forexample organic nitrates. The drawback of this treatment is thedevelopment of tolerance and a reduction of activity, and the higherdosage which is required because of this.

Various sGC stimulators which do not act via NO release were describedby Vesely in a series of publications. However, the compounds, most ofwhich are hormones, plant hormones, vitamins or natural compounds suchas, for example, lizard poisons, predominantly only have weak effects onthe cGMP formation in cell lysates. D. L. Vesely, Eur. J. Clin. Invest.,vol. 15, 1985, p. 258; D. L. Vesely, Biochem. Biophys. Res. Comm., vol.88, 1979, p. 1244. A stimulation of heme-free guanylate cyclase byprotoporphyrin IX was demonstrated by Ignarro et al., Adv. Pharmacol.,vol. 26, 1994, p. 35. Pettibone et al., Eur. J. Pharmacol., vol. 116,1985 p. 307, described an antihypertensive action of diphenyliodoniumhexafluorophosphate and attributed this to a stimulation of sGC.According to Yu et al., Brit. J. Pharmacol, vol. 114, 1995, p. 1587,isoliquiritigenin, which has a relaxing action on isolated rat aortas,also activates sGC. Ko et al., Blood vol. 84, 1994, p. 4226, Yu et al.,Biochem. J. vol. 306, 1995, p. 787, and Wu et al., Brit. J. Pharmacol.vol. 116, 1995, p. 1973, demonstrated a sGC-stimulating activity of1-benzyl-3-(5-hydroxymethyl-2-furyl)indazole and demonstrated anantiproliferative and thrombocyte-inhibiting action. Pyrazoles and fusedpyrazoles which exhibit a sGC-stimulating activity are described inEuropean Patent No. 908,456 and German Patent Application No.19,744,027.

It has now been found that the compounds of the present invention effecta strong activation of soluble guanylate cyclase and are therefore maybe suitable for the therapy and prophylaxis of disorders which areassociated with a low cGMP level.

SUMMARY OF THE INVENTION

The present invention relates to compounds which activate solubleguanylate cyclase and may be valuable pharmaceutically active compoundsfor the therapy and prophylaxis of diseases, for example forcardiovascular diseases such as hypertension, heart failure, pulmonaryhypertension, angina pectoris, diabetes, cardiac insufficiency,thrombosis, chronic kidney disease, fibrosis or atherosclerosis. Thecompounds of Formula (I)

are capable of modulating the body's production of cyclic guanosinemonophosphate (“cGMP”) and may be suitable for the therapy andprophylaxis of diseases which are associated with a disturbed cGMPbalance. The invention furthermore relates to processes for preparingcompounds of Formula (I), to the use of such compounds for the therapyand prophylaxis of the above mentioned diseases and for preparingcompounds for this purpose, and to pharmaceutical compositions whichcomprise compounds of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

In embodiment no. 1, the present invention provides a compound havingstructural Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X is C(H) or N;    -   each R¹ is independently halo, hydroxy, C₁-C₃ alkyl, C₃-C₆        cycloalkyl or —O—C₁-C₃ alkyl;    -   R² is:        -   (a.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl of R² is            unsubstituted or substituted by 1 to 6 moieties            independently selected from fluoro or —O—C₁-C₃ alkyl;        -   (b.) ring C², wherein ring C² is:            -   (i.) C₃-C₁₂ cycloalkyl;            -   (ii.) phenyl;            -   (iii.) a 5- or 6-membered monocyclic heteroaryl                containing 1 to 2 heteroatoms selected from N, O, or S;                or            -   (iv.) a 5- or 6-membered monocyclic heterocyclyl                containing 1 to 2 heteroatoms selected from N, O, or S;            -   wherein ring C² is unsubstituted or substituted by 1 to                3 moieties independently selected from halo, cyano,                C₁-C₃ alkyl, —O—C₁-C₃ alkyl, or oxo;    -   R⁴ is C₁-C₆ alkyl, CF₃, or C₃-C₆ cycloalkyl;    -   ring C³ is:        -   (a.) phenyl;        -   (b.) a 5- or 6-membered monocyclic heteroaryl or a 9- to            10-membered bicyclic        -   heteroaryl containing 1 to 3 heteroatoms selected from N, O,            or S;        -   (c.) a 5- or 6-membered monocyclic heterocyclyl containing 1            to 3 heteroatoms selected from N, O, or S; or        -   (d.) C₃-C₆ cycloalkyl;        -   each R^(a) is independently selected from halo, cyano, C₁-C₃            alkyl, —O—C₁-C₃ alkyl, oxo, or hydroxy;    -   Y is:        -   (a.) a bond;        -   (b.) a group of the formula

-   -   -   -   wherein R^(Y1) and R^(Y2) are independently H, C₁-C₃                alkyl, hydroxy, fluoro, C₁-C₃ hydroxyalkyl, or amino; or                alternatively R^(Y1) and R^(Y2), together with the                carbon atom to which they are attached form a C₃-C₆                cycloalkyl;            -   R^(Y3) and R^(Y4) are independently H, C₁-C₃ alkyl,                hydroxy, fluoro, or C₁-C₃ hydroxyalkyl; or alternatively                R^(Y3) and R^(Y4), together with the carbon atom to                which they are attached form a C₃-C₆ cycloalkyl;

        -   (c.) a group of the formula

-   -   -   (d.) ring A^(H), wherein ring A^(H) is C₃-C₆ cycloalkyl or            phenyl, wherein ring A^(H) is unsubstituted or substituted            by 1 to 3 moieties independently selected from halo or C₁-C₃            alkyl;        -   (e.) a group —CH═CH—; or        -   (f.) a group

-   -   Z is:        -   (a.) —CO₂H; (b.) —C(O)N(H)OH;

-   -   -   -   (f.) —SO₃H; (g.) —P(═O)(OH)₂; or (h.) —C(O)N(H)S(O)₂CH₃;

    -   the subscript m is 0, 1, or 2;

    -   the subscript p is 0, 1, 2, or 3;

    -   the subscript q is 0 or 1;

    -   the subscript r1 is 0, 1, 2, 3, or 4; and

    -   the subscript r2 is 0 or 1.

In the compounds of Formula (I), when Y is a group of the formula

the carbon atom bearing R^(Y3) and R^(Y4) (indicated by the arrow in thestructural formula below)

is bonded to a ring atom of ring C³, and the carbon atom bearing R^(Y1)and R^(Y2) is bonded to Z.

Similarly, in the compounds of Formula (I), when Y is a group of theformula

the leftmost carbon atom (indicated by the arrow in the structuralformula below)

is bonded to a ring atom of ring C³, and the carbon atom bearing R^(Y1)and R^(Y2) is bonded to Z.

Similarly, in the compounds of Formula (I), when Y is a group of theformula

the oxygen atom of the group Y is bonded to a ring atom of ring C³, andthe carbon atom in group Y is bonded to Z.

In embodiment no. 2, the present invention provides the compound havingstructural Formula (I), wherein

-   -   ring C³ is:        -   (a.) phenyl;        -   (b.) a 5- or 6-membered monocyclic heteroaryl containing 1            to 3 heteroatoms selected from N, O, or S;        -   (c.) a 5- or 6-membered monocyclic heterocyclyl containing 1            to 3 heteroatoms selected from N, O, or S; or        -   (d.) C₃-C₆ cycloalkyl;    -   each R^(a) is independently selected from halo, cyano, C₁-C₃        alkyl, —O—C₁-C₃ alkyl, or oxo;    -   Y is:        -   (a.) a bond;        -   (b.) a group of the formula

-   -   -   -   wherein R^(Y1) and R^(Y2) are independently H, C₁-C₃                alkyl, hydroxy, fluoro, or C₁-C₃ hydroxyalkyl; or                alternatively R^(Y1) and R^(Y2), together with the                carbon atom to which they are attached form a C₃-C₆                cycloalkyl;            -   R^(Y3) and R^(Y4) are independently H, C₁-C₃ alkyl,                hydroxy, fluoro, or C₁-C₃ hydroxyalkyl; or alternatively                R^(Y3) and R^(Y4), together with the carbon atom to                which they are attached form a C₃-C₆ cycloalkyl;

        -   (c.) a group of the formula

-   -   -    or        -   (d.) ring A^(H), wherein ring A^(H) is C₃-C₆ cycloalkyl or            phenyl, wherein ring A^(H) is unsubstituted or substituted            by 1 to 3 moieties independently selected from halo or C₁-C₃            alkyl; and            the remaining variables are as set forth in embodiment no.            1.

In embodiment no. 3, the present invention provides the compound havingstructural Formula (I), wherein the subscript q is 1, and R² is C₂-C₃alkyl which is unsubstituted or substituted by 1 to 5 fluoro; and theremaining variables are as set forth in embodiment no. 2.

In embodiment no. 4, the present invention provides the compound havingstructural Formula (I), wherein the subscript q is 1, and the group

is selected from —CH₂CH₂CF₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₃,—CH₂CH₂CH₂CH₂CH₃, or —CH₂CH₂OCH₃; and the remaining variables are as setforth in embodiment no. 2.

In embodiment no. 5, the present invention provides the compound havingstructural Formula (I), wherein the subscript q is 1, and the group

is —CH₂CH₂CF₂CF₃; and the remaining variables are as set forth inembodiment no. 2.

In embodiment no. 6, the present invention provides the compound havingstructural Formula (I), wherein the subscript q is 1;

-   -   R² is ring C²;        -   ring C² is phenyl, cyclohexyl, adamantyl, pyridyl, or            tetrahydropyranyl;        -   wherein ring C² is unsubstituted or independently            substituted by 1 to 3 fluoro or methyl; and    -   the remaining variables are as set forth in embodiment no. 2.

In embodiment no. 7, the present invention provides the compound havingstructural Formula (I), wherein ring C³ is phenyl, thiazolyl, oxazolyl,oxadiazolyl, triazolyl, or pyridyl; and the remaining variables are asset forth in embodiment no. 2.

In embodiment no. 8, the present invention provides the compound havingstructural Formula (I), wherein ring C³ is phenyl; and the remainingvariables are as set forth in embodiment no. 2.

In embodiment no. 9, the present invention provides the compound havingstructural Formula (I), wherein ring C³ is thiazolyl; and the remainingvariables are as set forth in embodiment no. 2.

In embodiment no. 10, the present invention provides the compound havingstructural Formula (I), wherein ring C³ is oxazolyl; and the remainingvariables are as set forth in embodiment no. 2.

In embodiment no. 11, the present invention provides the compound havingstructural Formula (I), wherein Y is the group of the formula

and the remaining variables are as set forth in embodiment no. 2.

In embodiment no. 12, the present invention provides the compound havingstructural Formula (I), wherein Y is the group of the formula

and the remaining variables are as set forth in embodiment no. 2.

In embodiment no. 13, the present invention provides the compound havingstructural Formula (I), wherein Y is as set forth in embodiment nos. 11or 12,

-   -   the subscript r1 is 1;    -   the subscript r2 is 0 (where present, as in embodiment no. 11);    -   R^(Y1) and R^(Y2) are independently H or C₁-C₃ alkyl;    -   the remaining variables are as set forth in embodiment no. 2.

In embodiment no. 14, the present invention provides the compound havingstructural Formula (I), wherein Z is (a.) —CO₂H; (b.) —C(O)N(H)OH; (c.)

or (d.)

and the remaining variables are as set forth in embodiment no. 2.

In embodiment no. 15, the present invention provides the compound havingstructural Formula (I), wherein Z is —CO₂H, and the remaining variablesare as set forth in embodiment no. 2.

In embodiment no. 16, the present invention provides the compound havingstructural Formula (I), wherein the subscript m is 0 or 1, and theremaining variables are as set forth in embodiment no. 2.

In embodiment no. 17, the present invention provides the compound havingstructural Formula (I), wherein R¹ is chloro or fluoro, and theremaining variables are as set forth in embodiment no. 2.

In embodiment no. 18, the present invention provides the compound havingstructural Formula (I), wherein X is C(H); and the remaining variablesare as set forth in embodiment no. 2.

In embodiment no. 19, the present invention provides the compound havingstructural Formula (I), wherein X is N; and the remaining variables areas set forth in embodiment no. 2.

In embodiment no. 20, the present invention provides the compound havingstructural Formula (I), wherein R⁴ is methyl or cyclopropyl, and theremaining variables are as set forth in embodiment no. 2.

In embodiment no. 21, the present invention provides the compound havingstructural Formula (I), wherein R⁴ is methyl, and the remainingvariables are as set forth in embodiment no. 2.

In embodiment no. 22, the present invention provides the compound havingstructural Formula (I), wherein

-   -   R² is C₂-C₃ alkyl which is unsubstituted or substituted by 1 to        5 fluoro:    -   ring C³ is as set forth as in embodiment no. 7;    -   Y is as set forth in embodiment no. 11;    -   Z is as set forth in embodiment no. 14;    -   R¹ is chloro or fluoro;    -   X is C(H) or N;    -   R⁴ is methyl or cyclopropyl;    -   the subscript m is 0 or 1;    -   the subscript q is 1; and    -   R^(a), R^(Y1), R^(Y2), R^(Y3), R^(Y4) and the subscripts p, r1,        and r2 are as set forth in embodiment no. 2.

In embodiment no. 23, the present invention provides the compound havingstructural Formula (I), wherein

the group

is —CH₂CH₂CF₂CF₃:

-   -   ring C³ is as set forth as in embodiment no. 8, 9, or 10;    -   R^(a) is fluoro, chloro, cyano, methyl, methoxy, or oxo;    -   Y is

-   -   R^(Y1) and R^(Y2) are independently H or C₁-C₃ alkyl;    -   Z is —CO₂H;    -   R¹ is chloro or fluoro;    -   X is C(H) or N;    -   R⁴ is methyl;    -   the subscript m is 0 or 1;    -   the subscript p is 0, 1, or 2;    -   the subscript q is 1; and    -   the subscript r1 is 1.

In embodiment no. 24, the compound of the Formula (I) has the Formula(IA)

wherein

-   -   X is C(H) or N;    -   R¹ is methyl or halo;    -   C³ is phenyl or thiazolyl;    -   R^(a) is methyl, cyano, or halo;    -   R^(Y1) and R^(Y2) are independently H or methyl;    -   the subscript m is 0 or 1; and    -   the subscript p is 0 or 1.

In embodiment no. 25, the compound of the Formula (I) has the Formula(IB)

wherein

-   -   X is C(H) or N;    -   R¹ is methyl or halo;    -   R² is ring C², wherein ring C² is:        -   (i.) C₃-C₁₂ cycloalkyl;        -   (ii.) phenyl;        -   (iii.) a 5- or 6-membered monocyclic heteroaryl containing 1            to 2 heteroatoms selected from N, O, or S; or        -   (iv.) a 5- or 6-membered monocyclic heterocyclyl containing            1 to 2 heteroatoms selected from N, O, or S;        -   wherein ring C² is unsubstituted or substituted by 1 to 3            moieties independently selected from halo, cyano, C₁-C₃            alkyl, —O—C₁-C₃ alkyl, or oxo;    -   C³ is phenyl, thiazolyl, or oxazolyl;    -   R^(a) is methyl, cyano, or halo;    -   R^(Y1) and R^(Y2) are independently H or methyl;    -   the subscript m is 0 or 1; and    -   the subscript p is 0 or 1.

In embodiment no. 26, the present invention provides a compound havingthe Formula (IB), wherein

-   -   R² is phenyl which is unsubstituted or substituted by 1 to 3        moieties independently selected from halo, cyano, C₁-C₃ alkyl,        or —O—C₁-C₃ alkyl; and    -   the remaining variables are as set forth in embodiment no. 25.

In embodiment no. 27, the present invention provides a compound havingthe Formula (IA), wherein

-   -   R¹ is halo;    -   C³ is phenyl, thiazolyl, oxazolyl, or benzothiazolyl;    -   R^(Y1) and R^(Y2) are independently H, methyl, or amino; and    -   X, R^(a), and the subscripts m and p are as set forth in        embodiment no. 24.

In embodiment no. 28, the present invention provides a compound havingthe Formula (IB), wherein

-   -   R¹ is halo;    -   C³ is phenyl, thiazolyl, oxazolyl, or benzothiazolyl;    -   R^(Y1) and R^(Y2) are independently H, methyl, or amino; and    -   X, R², R^(a), and the subscripts m and p are as set forth in        embodiment no. 25.

In embodiment no. 29, the present invention provides the compound havingthe formula (IB), wherein R² is phenyl and

-   -   X, R¹, C³, R^(a), R^(Y1), R^(Y2), the subscripts m and p are as        set forth in embodiment no. 25.

In another embodiment, the present invention provides a compoundselected from:

-   3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-bromophenyl)propanoic    acid;-   3-{4-[4-amino-2-{6-chloro-1-[(4-methylcyclohexyl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   3-{4-[4-amino-2-{6-chloro-1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(6-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(3-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)propanoic    acid;-   3-(4-{4-amino-2-(1-butyl-6-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-(1-butyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2-methylpropanoic    acid;-   3-(4-{4-amino-2-[5-fluoro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-5-methyl-2-[6-methyl-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(3-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(3-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[1-(2,3-difluoro-4-methylbenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoic    acid;-   3-(3-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)acetic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)propanoic    acid;-   2-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropanoic    acid;-   1-[(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)methyl]cyclopropanecarboxylic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2-methylpropanoic    acid;-   2-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1H-1,2,3-triazol-1-yl}acetic    acid;-   3-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1H-1,2,3-triazol-1-yl}propanoic    acid;-   3-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}-2,2-dimethylpropanoic    acid;-   3-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   3-(3-{4-amino-2-[6-chloro-1-(2-methoxyethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(2-methoxyethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   3-{4-[4-amino-2-(6-chloro-1-pentyl-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(cyclohexylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-{4-[4-amino-2-(6-chloro-1-hexyl-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   3-(4-{4-amino-2-[6-fluoro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(3-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   4-(2-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)butanoic    acid;-   3-(2-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)propanoic    acid;-   2-(2-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)acetic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(4,4-dimethylpentyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(3-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)propanoic    acid;-   4-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)butanoic    acid;-   3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(4-[4-amino-2-{6-chloro-1-[(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)propanoic    acid;-   3-(4-[4-amino-2-{6-chloro-1-[(4,4-difluorocyclohexyl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)propanoic    acid;-   3-(4-{4-amino-2-[1-(2-fluorobenzyl)-6-methyl-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(3-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(2-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(4-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(4-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(2-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{2-[1-(adamantan-1-ylmethyl)-6-chloro-1H-indazol-3-yl]-4-amino-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)    propanoic acid;-   3-(4-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(2-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-2-[5-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(2-{4-amino-2-[5-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[1-(2,3-difluoro-4-methylbenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)acetic    acid;-   3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-3-methylbutanoic    acid;-   2-(2-{-4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)cyclopropanecarboxylic    acid;-   1-[(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)methyl]cyclopropanecarboxylic    acid;-   3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)propanoic    acid;-   (2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-4-methyl-1,3-thiazol-5-yl)acetic    acid;-   3-(2-{4-amino-2-[5-fluoro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[5-fluoro-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-{2-[4-amino-2-(1-butyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)propanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)benzoic    acid;-   4-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-5-methyl-1,3-thiazol-4-yl)benzoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-5-cyclopropyl-2-[5-fluoro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-N-hydroxy-2,2-dimethylpropanamide;-   [5-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-oxo-1,3,4-oxadiazol-3(2H)-yl]acetic    acid;-   2-[5-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-oxo-1,3,4-oxadiazol-3(2H)-yl]-2-methylpropanoic    acid;-   (3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)glycine;-   2-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamido)-2-methylpropanoic    acid;-   (3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-D-alanine;-   (3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-L-alanine;-   (2R)-2-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamido)butanoic    acid;-   (2S)-2-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamido)butanoic    acid;-   (3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-D-serine;-   (3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-D-threonine;-   N-((2H-tetrazol-5-yl)methyl)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamide;-   3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2H-1,2,3-triazol-2-yl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-5-hydroxy-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-{4-[4-amino-2-(1-butyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(2H-tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   4-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic    acid;-   (4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic    acid;-   4-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic    acid;-   4-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic    acid;-   2-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic    acid;-   2-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic    acid;-   3-(6-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-cyanophenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylphenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-hydroxyphenyl)propanoic    acid;-   (5S)-3-{2-[4-amino-5-methyl-6-oxo-2-{1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}-2,2-dimethylpropanoic    acid;-   3-{2-[4-amino-5-methyl-6-oxo-2-{1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   (5S)-3-{2-[4-amino-5-methyl-2-{1-[4-methylcyclohexylmethyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}-2,2-dimethylpropanoic    acid;-   3-{2-[4-amino-5-methyl-2-{1-[4-methylcyclohexylmethyl]-1H-pyrazolo[3,4-b]pyridin-3-yl}-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   4-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-difluorobutanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-2-yl)-2,2-dimethylpropanoic    acid;-   3-(6-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)propanoic    acid;-   2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-benzothiazole-5-carboxylic    acid;-   3-(6-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)-2,2-dimethylpropanoic    acid;-   3-{2-[4-amino-2-{6-chloro-1-[4-methylcyclohexylmethyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   (5S)-3-{2-[4-amino-2-{6-fluoro-1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}-2,2-dimethylpropanoic    acid;-   3-{2-[4-amino-2-{6-fluoro-1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   4-(2-{4-amino-2-[6-fluoro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-difluorobutanoic    acid;-   (5S)-3-{2-[4-amino-2-{6-fluoro-1-[4-methylcyclohexylmethyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}-2,2-dimethylpropanoic    acid;-   3-{2-[4-amino-2-{6-fluoro-1-[4-methylcyclohexylmethyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-cyclopropyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-5-cyclopropyl-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropanoic    acid;-   2-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-2-yl)-2,2-dimethylpropanoic    acid;-   4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridine-2-carboxylic    acid;-   3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropanoic    acid;-   4-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)benzoic    acid;-   4-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)benzoic    acid;-   3-(4-{4-amino-5-cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(2-{4-amino-2-[1-(3-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[1-(3-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[1-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[1-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[1-(cyclopentylmethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[1-(cyclopentylmethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoic    acid;-   4-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)benzoic    acid;-   (2E)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)prop-2-enoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-cyclopropyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(cyclohexylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(cyclopentylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(cyclopentylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(cyclopentylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-{4-[4-amino-2-{6-chloro-1-[(3,3-difluorocyclobutyl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   4-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)benzoic    acid;-   4-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)benzoic    acid;-   4-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylbutanoic    acid;-   4-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylbutanoic    acid;-   2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-benzoxazole-5-carboxylic    acid;-   3-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-5-methyl-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-D-alanine;-   3-(2-{4-amino-2-[6-chloro-1-(4-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(4-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-5-methyl-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   4-(2-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylbutanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2,4-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(2,4-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2,3-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(2,3-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-{2-[4-amino-2-{6-chloro-1-[(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   (S)-3-{2-[4-amino-2-{6-chloro-1-[(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2-fluoro-3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(2-fluoro-3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2,3,6-trifluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(2,3,6-trifluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoic    acid;-   3-(4-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropanoic    acid;-   4-(2-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylbutanoic    acid;-   (S)-3-(2-{4-amino-2-[6-fluoro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-fluoro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   4-(2-{4-amino-2-[6-fluoro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylbutanoic    acid;-   4-(2-{4-amino-2-[6-fluoro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylbutanoic    acid;-   3-(2-{4-amino-2-[6-fluoro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-5-methyl-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[1-(2,3-difluorobenzyl)-6-fluoro-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[1-(2,3-difluorobenzyl)-6-fluoro-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[1-(cyclohexylmethyl)-6-fluoro-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[1-(cyclohexylmethyl)-6-fluoro-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)acetic    acid;-   4-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylbutanoic    acid;-   4-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylbutanoic    acid;-   4-{2-[4-amino-2-{6-chloro-1-[(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}-2,2-dimethylbutanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(3,3-dimethylbutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoic    acid;-   (S)-3-(4-{4-amino-2-[1-(3,3-dimethylbutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(4-{4-amino-2-[6-fluoro-1-(2-fluoro-3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-fluoro-1-(2-fluoro-3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[6-chloro-1-(2-fluoro-5-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}    1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(2-fluoro-5-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}    1,3-thiazol-4-yl)-2,2-dimethylpropanoic acid;-   3-(2-{4-amino-2-[6-chloro-1-((3-fluoro-4-methylpyridin-2-yl)methyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}    1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-((3-fluoro-4-methylpyridin-2-yl)methyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}    1,3-thiazol-4-yl)-2,2-dimethylpropanoic acid;-   (2E)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)prop-2-enoic    acid;-   (2E)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)prop-2-enoic    acid;-   2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridine-4-carboxylic    acid;-   4-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylbutanoic    acid;-   (S)-3-(4-{4-amino-2-[1-(4-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(2-{4-amino-2-[1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   3-(2-{4-amino-2-[1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(2,3,6-trifluorobenzyl)-1H-indazol-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-5-methyl-2-[1-(3-methylbenzyl)-1H-indazol-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(2-{4-amino-5-methyl-2-[1-(3-methylbenzyl)-1H-indazol-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-2-[1-(cyclopentylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   3-(2-{4-amino-2-[1-(cyclohexylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (5S)-3-{2-[4-amino-5-methyl-6-oxo-2-{1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol-3-yl}-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}-2,2-dimethylpropanoic    acid;-   3-{2-[4-amino-5-methyl-6-oxo-2-{1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol-3-yl}-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   3-{2-[4-amino-5-methyl-2-{1-[-4-methylcyclohexylmethyl]-1H-indazol-3-yl}-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   (S)-3-{4-[4-amino-2-{1-[(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   3-(2-{4-amino-2-[1-(2-fluoro-3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-D-alanine;-   3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-imidazol-4-yl)propanoic    acid;-   (S)-4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-methyl-2-(2H-tetrazol-5-yl)propyl]thiazol-2-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   (S)-4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(2H-tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   (S)-4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-methyl-2-(2H-tetrazol-5-yl)propyl]-1,3-thiazol-2-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-methyl-2-(2H-tetrazol-5-yl)propyl]-1,3-oxazol-2-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   (S)-4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5-{4-[2-(2H-tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   (S)-4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5-{4-[2-methyl-2-(2H-tetrazol-5-yl)propyl]-1,3-thiazol-2-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   (S)-4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(2H-tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   5-[4-(2H-tetrazol-5-yl)pyridin-2-yl]-4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   5-{4-[(2H-tetrazol-5-yl)methyl]phenyl}-4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   (S)-5-{4-[2-(2H-tetrazol-5-yl)ethyl]phenyl}-4-amino-2-{1-[(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   5-{5-[2-(2H-tetrazol-5-yl)ethyl]pyridin-2-yl}-4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   5-{5-[2-(2H-tetrazol-5-yl)ethyl]pyridin-2-yl}-4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-methyl-2-(2H-tetrazol-5-yl)propyl]oxazol-2-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-[3-(1H-tetrazol-5-yl)phenyl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-[4-(1H-tetrazol-5-yl)phenyl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-5-[3-(1H-tetrazol-5-yl)phenyl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   4-amino-5-methyl-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[3-(2H-tetrazol-5-yl)phenyl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   5-[6-(2H-tetrazol-5-yl)pyridin-2-yl]-4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   6-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridine-3-carboxylic    acid;-   6-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}picolinic    acid;-   (S)-4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   [2-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)ethyl]phosphonic    acid;-   2-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)ethanesulfonic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-N-(methylsulfonyl)propanamide;-   (4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy)acetic    acid;-   3-[1-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyrrolidin-3-yl]propanoic    acid;-   3-(1-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}piperidin-4-yl)propanoic    acid;-   3-(4-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)propanoic    acid; or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compoundselected from:

-   (R)-3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-bromophenyl)propanoic    acid;-   (5R)-3-{4-[4-amino-2-{6-chloro-1-[(4-methylcyclohexyl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (R)-3-{4-[4-amino-2-{6-chloro-1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (R)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(6-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(4-{4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-2,3-dihydro-H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(3-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (R)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)propanoic    acid;-   (R)-3-(4-{4-amino-2-(1-butyl-6-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-(1-butyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (5R)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2-methylpropanoic    acid;-   (R)-3-(4-{4-amino-2-[5-fluoro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-5-methyl-2-[6-methyl-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(3-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(3-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[1-(2,3-difluoro-4-methylbenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoic    acid;-   (R)-3-(3-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (R)-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)acetic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)propanoic    acid;-   (R)-2-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropanoic    acid;-   (R)-1-[(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)methyl]cyclopropanecarboxylic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (5R)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2-methylpropanoic    acid;-   (R)-2-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1H-1,2,3-triazol-1-yl}acetic    acid;-   (R)-3-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1H-1,2,3-triazol-1-yl}propanoic    acid;-   (R)-3-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}-2,2-dimethylpropanoic    acid;-   (R)-3-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (R)-3-(3-{4-amino-2-[6-chloro-1-(2-methoxyethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(2-methoxyethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (R)-3-{4-[4-amino-2-(6-chloro-1-pentyl-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(cyclohexylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-{4-[4-amino-2-(6-chloro-1-hexyl-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-fluoro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(3-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-4-(2-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)butanoic    acid;-   (R)-3-(2-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)propanoic    acid;-   (R)-2-(2-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)acetic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(4,4-dimethylpentyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(3-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)propanoic    acid;-   (R)-4-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)butanoic    acid;-   (R)-3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(4-[4-amino-2-{6-chloro-1-[(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)propanoic    acid;-   (R)-3-(4-[4-amino-2-{6-chloro-1-[(4,4-difluorocyclohexyl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-6-methyl-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(3-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(2-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(4-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(4-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(2-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(4-{2-[1-(adamantan-1-ylmethyl)-6-chloro-1H-indazol-3-yl]-4-amino-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)    propanoic acid;-   (R)-3-(4-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(2-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(4-{4-amino-2-[5-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(2-{4-amino-2-[5-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-2-[1-(2,3-difluoro-4-methylbenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)acetic    acid;-   (R)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-3-methylbutanoic    acid;-   (5R)-2-(2-{-4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)cyclopropanecarboxylic    acid;-   (R)-1-[(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)methyl]cyclopropanecarboxylic    acid;-   (R)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)propanoic    acid;-   (R)-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-4-methyl-1,3-thiazol-5-yl)acetic    acid;-   (R)-3-(2-{4-amino-2-[5-fluoro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-2-[5-fluoro-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-{2-[4-amino-2-(1-butyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)propanoic    acid;-   (R)-3-(2-{4-amino-2-[6-chloro-l-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)benzoic    acid;-   (R)-4-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-5-methyl-1,3-thiazol-4-yl)benzoic    acid;-   (R)-3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-5-cyclopropyl-2-[5-fluoro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (R)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-N-hydroxy-2,2-dimethylpropanamide;-   (R)-[5-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-oxo-1,3,4-oxadiazol-3(2H)-yl]acetic    acid;-   (R)-2-[5-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-oxo-1,3,4-oxadiazol-3(2H)-yl]-2-methylpropanoic    acid;-   (R)-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)glycine;-   (R)-2-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamido)-2-methylpropanoic    acid;-   (5R)-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-D-alanine;-   (5R)-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-L-alanine;-   (5R)-(2R)-2-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamido)butanoic    acid;-   (5R)-(2S)-2-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamido)butanoic    acid;-   (5R)-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-D-serine;-   (5R)-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-D-threonine;-   (R)—N-((2H-tetrazol-5-yl)methyl)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamide;-   (R)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2H-1,2,3-triazol-2-yl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-5-hydroxy-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (R)-3-{4-[4-amino-2-(1-butyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (R)-4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(2H-tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   (R)-4-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic    acid;-   (R)-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic    acid;-   (R)-4-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic    acid;-   (R)-4-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic    acid;-   (R)-2-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic    acid;-   (R)-2-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic    acid;-   (R)-3-(6-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-cyanophenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylphenyl)propanoic    acid;-   (R)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-hydroxyphenyl)propanoic    acid;    or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compoundselected from:

-   (S)-3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)oxazol-4-yl}-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-bromophenyl)propanoic    acid;-   (5S)-3-{4-[4-amino-2-{6-chloro-1-[(4-methylcyclohexyl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (S)-3-{4-[4-amino-2-{6-chloro-1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (S)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(6-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(3-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)propanoic    acid;-   (S)-3-(4-{4-amino-2-(1-butyl-6-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-(1-butyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (5    S)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2-methylpropanoic    acid;-   (S)-3-(4-{4-amino-2-[5-fluoro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-5-methyl-2-[6-methyl-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(3-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(3-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[1-(2,3-difluoro-4-methylbenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzoic    acid;-   (S)-3-(3-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (S)-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)acetic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)propanoic    acid;-   (S)-2-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropanoic    acid;-   (S)-1-[(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)methyl]cyclopropanecarboxylic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (5    S)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2-methylpropanoic    acid;-   (S)-2-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1H-1,2,3-triazol-1-yl}acetic    acid;-   (S)-3-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1H-1,2,3-triazol-1-yl}propanoic    acid;-   (S)-3-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}-2,2-dimethylpropanoic    acid;-   (S)-3-{4-[4-amino-2-(1-butyl-6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (S)-3-(3-{4-amino-2-[6-chloro-1-(2-methoxyethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(2-methoxyethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoic    acid;-   (S)-3-{4-[4-amino-2-(6-chloro-1-pentyl-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(cyclohexylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-{4-[4-amino-2-(6-chloro-1-hexyl-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-fluoro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(3-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-4-(2-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)butanoic    acid;-   (S)-3-(2-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)propanoic    acid;-   (S)-2-(2-{4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)acetic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(4,4-dimethylpentyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(3-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)propanoic    acid;-   (S)-4-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)butanoic    acid;-   (S)-3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-[4-amino-2-{6-chloro-1-[(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)propanoic    acid;-   (S)-3-(4-[4-amino-2-{6-chloro-1-[(4,4-difluorocyclohexyl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-6-methyl-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(3-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(2-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(4-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(4-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(2-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(4-{2-[1-(adamantan-1-ylmethyl)-6-chloro-1H-indazol-3-yl]-4-amino-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)    propanoic acid;-   (S)-3-(4-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(2-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-2-[5-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(2-{4-amino-2-[5-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[1-(2,3-difluoro-4-methylbenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)acetic    acid;-   (S)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-3-methylbutanoic    acid;-   (5    S)-2-(2-{-4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)cyclopropanecarboxylic    acid;-   (S)-1-[(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)methyl]cyclopropanecarboxylic    acid;-   (S)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)propanoic    acid;-   (S)-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-4-methyl-1,3-thiazol-5-yl)acetic    acid;-   (S)-3-(2-{4-amino-2-[5-fluoro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[5-fluoro-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-{2-[4-amino-2-(1-butyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)propanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)benzoic    acid;-   (S)-4-(2-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-5-methyl-1,3-thiazol-4-yl)benzoic    acid;-   (S)-3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-5-cyclopropyl-2-[5-fluoro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoic    acid;-   (S)-3-(2-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-N-hydroxy-2,2-dimethylpropanamide;-   (S)-[5-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-oxo-1,3,4-oxadiazol-3    (2H)-yl]acetic acid;-   (S)-2-[5-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-oxo-1,3,4-oxadiazol-3(2H)-yl]-2-methylpropanoic    acid;-   (S)-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)glycine;-   (S)-2-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamido)-2-methylpropanoic    acid;-   (5    S)-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-D-alanine;-   (5    S)-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-L-alanine;-   (5S)-(2R)-2-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamido)butanoic    acid;-   (5S)-(2S)-2-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamido)butanoic    acid;-   (5    S)-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-D-serine;-   (5    S)-(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)-D-threonine;-   (S)—N-((2H-tetrazol-5-yl)methyl)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamide;-   (S)-3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2H-1,2,3-triazol-2-yl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-5-hydroxy-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic    acid;-   (S)-3-{4-[4-amino-2-(1-butyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic    acid;-   (S)-4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(2H-tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one;-   (S)-4-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic    acid;-   (S)-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic    acid;-   (S)-4-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic    acid;-   (S)-4-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic    acid;-   (S)-2-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic    acid;-   (S)-2-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic    acid;-   (S)-3-(6-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-cyanophenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylphenyl)propanoic    acid;-   (S)-3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-hydroxyphenyl)propanoic    acid; or-   a pharmaceutically acceptable salt thereof.

The present invention includes the pharmaceutically acceptable salts ofthe compounds defined herein, including the pharmaceutically acceptablesalts of all structural formulas, embodiments and classes definedherein. Reference to the compounds of structural Formula (I) includesthe compounds of other generic structural Formulas and embodiments thatfall within the scope of Formula (I), including but not limited to thecompounds of Formulas (IA) or (IB).

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, and the like, means carbon chains which may be linear orbranched, or combinations thereof, containing the indicated number ofcarbon atoms. If no number is specified, 1-6 carbon atoms are intendedfor linear and 3-7 carbon atoms for branched alkyl groups. Examples ofalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- andtert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and the like.

“Alkoxy” and “alkyl-O—” are used interchangeably and refer to an alkylgroup linked to oxygen.

“Alkyl-NH—” refers to an alkyl group linked to an NH group. Examples ofalkyl-NH-include methyl-amino or methyl-NH— and ethyl-amino orethyl-NH—.

“Aryl” means phenyl or naphthyl.

“Haloalkyl” include mono-substituted as well as multiple halosubstituted alkyl groups, up to perhalo substituted alkyl. For example,halomethyl, 1,1-difluoroethyl, trifluoromethyl or1,1,1,2,2-pentafluorobutyl are included.

“Haloalkoxy” and “haloalkyl-O” are used interchangeably and refer tohalo substituted alkyl groups or “haloalkyl” linked through the oxygenatom. Haloalkoxy include mono-substituted as well as multiple halosubstituted alkoxy groups, up to perhalo substituted alkoxy. Forexample, trifluoromethoxy is included.

“Cycloalkyl” means a saturated cyclic hydrocarbon radical having thenumber of carbon atoms designated if no number of atoms is specified,3-12 carbon atoms are intended, forming 1-3 carbocyclic rings that arefused. “Cycloalkyl” also includes monocyclic rings fused to an arylgroup in which the point of attachment is on the non-aromatic portion.Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, tetrahydronaphthyl, adamantyl,decahydronaphthyl, indanyl and the like.

“Cycloalkoxy” and “cycloalkyl-O” are used interchangeably and refer to acycloalkyl group, as defined above, linked to oxygen.

“Heterocyclyl” “heterocycle” or “heterocyclic” refers to nonaromaticmonocyclic ring structures in which one or more atoms in the ring, theheteroatom(s), is an element other than carbon. Such nonaromatic cyclicring structures can be saturated or unsaturated. Heteroatoms aretypically O, S or N atoms. Examples of heterocyclyl groups include:piperidine, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl,azetidinyl, oxiranyl, or aziridinyl, and the like.

“Heteroaryl” refers to an aromatic monocyclic and bicyclic ringstructures in which one or more atoms in the ring, the heteroatom(s), isan element other than carbon. Heteroatoms are typically O, S, or Natoms. Examples of heteroaromatic groups include: pyridinyl,pyrimidinyl, pyrrolyl, pyridazinyl, isoxazolyl, thiazolyl, oxazolyl,indolyl, benzoxazolyl, benzothiazolyl, or imidazolyl.

“Halogen” (or “halo”) unless otherwise indicated, includes fluorine(fluoro), chlorine (chloro), bromine (bromo) and iodine (iodo). In oneembodiment, halo is fluoro (—F) or chloro (—Cl).

When any variable (e.g., R¹, R², etc.) occurs more than one time in anyconstituent or in Formula (I) or other generic formulas herein, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. Inchoosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e., R¹, R²,etc., are to be chosen in conformity with well-known principles ofchemical structure connectivity and stability. Unless expressly statedto the contrary, substitution by a named substituent is permitted on anyatom in a ring (e.g., aryl, a heteroaryl ring, or a saturatedheterocyclic ring) provided such ring substitution is chemically allowedand results in a stable compound. A “stable” compound is a compoundwhich can be prepared and isolated and whose structure and propertiesremain or can be caused to remain essentially unchanged for a period oftime sufficient to allow use of the compound for the purposes describedherein (e.g., therapeutic or prophylactic administration to a subject).

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substituent. Where multiple substituent moietiesare disclosed or claimed, the substituted compound can be independentlysubstituted by one or more of the disclosed or claimed substituentmoieties, singly or plurally. By independently substituted, it is meantthat the (two or more) substituents can be the same or different.

Unless expressly depicted or described otherwise, variables depicted ina structural formula with a “floating” bond, such as R¹ in Formula (I),are permitted on any available carbon atom in the ring to which thevariable is attached. When a moiety is noted as being “optionallysubstituted” in Formula (I) or any embodiment thereof, it means thatFormula (I) or the embodiment thereof encompasses compounds that containthe noted substituent (or substituents) on the moiety and also compoundsthat do not contain the noted substituent (or substituents) on themoiety.

Compounds of Formula (I) may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereoisomeric mixtures and individual diastereoisomers. Centers ofasymmetry that are present in the compounds of Formula (I) can allindependently of one another have S configuration or R configuration.The compounds of this invention include all possible enantiomers anddiastereomers and mixtures of two or more stereoisomers, for examplemixtures of enantiomers and/or diastereomers, in all ratios. Thus,enantiomers are a subject of the invention in enantiomerically pureform, both as levorotatory and as dextrorotatory antipodes, in the formof racemates and in the form of mixtures of the two enantiomers in allratios. In the case of a cis/trans isomerism the invention includes boththe cis form and the trans form as well as mixtures of these forms inall ratios. The present invention is meant to comprehend all suchstereoisomeric forms of the compounds of Formula (I). Where a structuralformula or chemical name specifies a particular configuration at astereocenter, the enantiomer or stereoisomer of the compound resultingfrom that specified stereocenter is intended. Where a structural formulaof the compounds of Formula (I) indicates a straight line at a chiralcenter, the structural formula includes both the S and R stereoisomersassociated with the chiral center and mixtures thereof.

Compounds of Formula (I) may be separated into their individualdiastereoisomers by, for example, fractional crystallization from asuitable solvent, for example methanol or ethyl acetate or a mixturethereof, or via chiral chromatography using an optically activestationary phase. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing anasymmetric center of known absolute configuration. Vibrational circulardichroism (VCD) may also be used to determine the absolutestereochemistry. Alternatively, any stereoisomer or isomers of acompound of Formula (I) may be obtained by stereospecific synthesisusing optically pure starting materials or reagents of known absoluteconfiguration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereoisomeric mixture, followed by separation of the individualdiastereoisomers by standard methods, such as fractional crystallizationor chromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

For compounds of Formula (I) described herein which contain olefinicdouble bonds, unless specified otherwise, they are meant to include bothE and Z geometric isomers.

Some of the compounds described herein may exist as tautomers which havedifferent points of attachment of hydrogen accompanied by one or moredouble bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of Formulas I of the presentinvention.

In the compounds of Formula (I), the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominately found in nature. The present invention as described andclaimed herein is meant to include all suitable isotopic variations ofthe compounds of Formula (I) and embodiments thereof. For example,different isotopic forms of hydrogen (H) include protium (¹H) anddeuterium (²H, also denoted herein as D). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds of Formula (I), can be prepared withoutundue experimentation by conventional techniques well known to thoseskilled in the art or by processes analogous to those described in theSchemes and Examples herein using appropriate isotopically-enrichedreagents and/or intermediates.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids. When thecompound of the present invention is acidic, its corresponding salt canbe conveniently prepared from pharmaceutically acceptable non-toxicbases, including inorganic bases and organic bases. Salts derived fromsuch inorganic bases include aluminum, ammonium, calcium, copper (ic andous), ferric, ferrous, lithium, magnesium, manganese (ic and ous),potassium, sodium, zinc and the like salts. Preferred are the ammonium,calcium, magnesium, potassium and sodium salts. Salts prepared frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines derived from both naturallyoccurring and synthetic sources. Pharmaceutically acceptable organicnon-toxic bases from which salts can be formed include, for example,arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine,dicyclohexylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine and thelike.

When the compound of the present invention is basic, its correspondingsalt can be conveniently prepared from pharmaceutically acceptablenon-toxic inorganic and organic acids. Such acids include, for example,acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid and the like. Preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. If thecompounds of Formula (I) simultaneously contain acidic and basic groupsin the molecule the invention also includes, in addition to the saltforms mentioned, inner salts or betaines (zwitterions). Salts can beobtained from the compounds of Formula (I) by customary methods whichare known to the person skilled in the art, for example, by combinationwith an organic or inorganic acid or base in a solvent or dispersant, orby anion exchange or cation exchange from other salts. The presentinvention also includes all salts of the compounds of Formula (I) which,owing to low physiological compatibility, are not directly suitable foruse in pharmaceuticals but which can be used, for example, asintermediates for chemical reactions or for the preparation ofpharmaceutically acceptable salts.

Furthermore, compounds of the present invention may exist in amorphousform and/or one or more crystalline forms, and as such all amorphous andcrystalline forms and mixtures thereof of the compounds of Formula (I),including the Examples, are intended to be included within the scope ofthe present invention. In addition, some of the compounds of the instantinvention may form solvates with water (i.e., a hydrate) or commonorganic solvents such as but not limited to ethyl acetate. Such solvatesand hydrates, particularly the pharmaceutically acceptable solvates andhydrates, of the instant compounds are likewise encompassed within thescope of this invention, along with un-solvated and anhydrous forms.

Any pharmaceutically acceptable pro-drug modification of a compound ofthis invention which results in conversion in vivo to a compound withinthe scope of this invention is also within the scope of this invention.For example, esters can optionally be made by esterification of anavailable carboxylic acid (—COOH) group or by formation of an ester onan available hydroxy group in a compound. Similarly, labile amides canbe made. Pharmaceutically acceptable esters or amides of the compoundsof this invention may be prepared to act as pro-drugs which can behydrolyzed back to an acid (or —COO— depending on the pH of the fluid ortissue where conversion takes place) or hydroxy form particularly invivo and as such are encompassed within the scope of this invention.Included are those esters and acyl groups known in the art for modifyingthe solubility or hydrolysis characteristics for use assustained-release or prodrug formulations. Also, in the case of acarboxylic acid (—COOH) or alcohol group being present in the compoundsof the present invention, pharmaceutically acceptable esters ofcarboxylic acid derivatives, such as methyl, ethyl, orpivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed.

The present invention also relates to processes for the preparation ofthe compounds of Formula (I) which are described in the following and bywhich the compounds of the invention are obtainable.

The compounds of Formula (I) according to the invention effect anincrease of cGMP concentration via the activation of the solubleguanylate cyclase (sGC), and they therefore may be useful agents for thetherapy and prophylaxis of disorders which are associated with a low ordecreased cGMP level or which are caused thereby, or for whose therapyor prophylaxis an increase of the present cGMP level is desired. Theactivation of the sGC by the compounds of Formula (I) can be examined,for example, in the cell-based sGC functional assay described in theBiological Assays below.

The compounds of Formula (I) bind with high potency to sGC. High potencycompounds are preferred to enable administration of low human doses. Forinhaled delivery applications, high potency compounds may enable use oflow human doses, and allow for formulation within the restraints of aninhaled delivery device.

The binding potencies of the compounds of Formula (I) can be determinedin a competitive binding assay that uses a labeled sGC ligand. TheBiological Assays section below describes an example of a competitivebinding assay used to determine the compounds' abilities to displace aradioligand that binds to purified recombinant sGC.

The activity of the compounds in vivo can be assessed in various animalmodels of hypertension, such as by measuring their acute efficacy inspontaneously hypertensive rats (SHR). In addition, the activity of thecompounds can be assessed by measuring the pulmonary and systolic bloodpressure in a hypoxia-induced pulmonary hypertension rat model followingintratracheal administration of sGC stimulator compounds. In oneembodiment, preferred compounds of the Formula (I) achieve a minimumdecrease in pulmonary arterial pressure of ≥15 mmHg for thecorresponding smaller decrease in systolic blood pressure in thehypoxia-induced pulmonary hypertension rat model. For instance, in oneembodiment, preferred compounds of the Formula (I) achieve a minimumdecrease in pulmonary arterial pressure of ≥15 mmHg for thecorresponding decrease in systolic blood pressure, which decrease is ≤10mmHg in this assay. The Biological Assays section below describes thesein vivo models of hypertension.

The terms “therapeutically effective (or efficacious) amount” andsimilar descriptions such as “an amount efficacious for treatment” areintended to mean that amount of a pharmaceutical drug that will elicitthe biological or medical response of a tissue, a system, animal orhuman that is being sought by a researcher, veterinarian, medical doctoror other clinician. In a preferred embodiment, the term “therapeuticallyeffective amount” means an amount of a pharmaceutical drug thatalleviates at least one clinical symptom in a human patient. The terms“prophylactically effective (or efficacious) amount” and similardescriptions such as “an amount efficacious for prevention” are intendedto mean that amount of a pharmaceutical drug that will prevent or reducethe risk of occurrence of the biological or medical event that is soughtto be prevented in a tissue, a system, animal or human by a researcher,veterinarian, medical doctor or other clinician. As an example, thedosage a patient receives can be selected so as to achieve the desiredreduction in blood pressure; the dosage a patient receives may also betitrated over time in order to reach a target blood pressure. The dosageregimen utilizing a compound of the instant invention is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the potency of the compound chosen to beadministered; the route of administration; and the renal and hepaticfunction of the patient. A consideration of these factors is well withinthe purview of the ordinarily skilled clinician for the purpose ofdetermining the therapeutically effective or prophylactically effectivedosage amount needed to prevent, counter, or arrest the progress of thecondition. It is understood that a specific daily dosage amount cansimultaneously be both a therapeutically effective amount, e.g., fortreatment of hypertension, and a prophylactically effective amount,e.g., for prevention of myocardial infarction.

Disorders and pathological conditions which are associated with a lowcGMP level or in which an increase of the cGMP level is desired and forwhose therapy and prophylaxis it is possible to use compounds of Formula(I) are, for example, cardiovascular diseases, such as endothelialdysfunction, diastolic dysfunction, atherosclerosis, hypertension, heartfailure, pulmonary hypertension (WHO Groups 1-5), which includespulmonary arterial hypertension (PAH), stable and unstable anginapectoris, thromboses, restenoses, myocardial infarction, strokes,cardiac insufficiency, fibrosis or pulmonary hypertonia, or, forexample, erectile dysfunction, asthma (e.g., bronchial asthma), acuterespiratory distress syndrome (ARDS), acute lung injury, pulmonaryfibrosis, chronic kidney disease, chronic kidney insufficiency, cysticfibrosis, interstitial lung disease, sickle cell anemia, scleroderma,Raynaud's Syndrome, and diabetes. Compounds of Formula (I) canadditionally be used in the therapy of cirrhosis of the liver and alsofor improving a restricted memory performance or ability to learn.

In one embodiment of the invention, the compounds of Formula (I) may beused for treating cardiovascular disease, endothelial dysfunction,diastolic dysfunction, atherosclerosis, hypertension, heart failure,pulmonary hypertension (WHO groups I, II, III, IV), angina pectoris,thrombosis, restenosis, myocardial infarction, stroke, cardiacinsufficiency, fibrosis, pulmonary hypertonia, erectile dysfunction,asthma, chronic kidney disease, diabetes, diabetic retinopathy,cirrhosis of the liver, chronic obstructive pulmonary disease (COPD),acute respiratory distress syndrome, acute lung injury, pulmonaryfibrosis, cystic fibrosis, or interstitial lung disease.

The compounds of Formula (I) and their pharmaceutically acceptable saltscan be administered to animals, preferably to mammals, and in particularto humans, as pharmaceuticals by themselves, in mixtures with oneanother or in the form of pharmaceutical compositions. The term“patient” includes animals, preferably mammals and especially humans,who use the instant active agents for the prevention or treatment of amedical condition. Administering of the drug to the patient includesboth self-administration and administration to the patient by anotherperson. The patient may be in need of, or desire, treatment for anexisting disease or medical condition, or may be in need of or desireprophylactic treatment to prevent or reduce the risk of occurrence ofsaid disease or medical condition. As used herein, a patient “in need”of treatment of an existing condition or of prophylactic treatmentencompasses both a determination of need by a medical professional aswell as the desire of a patient for such treatment.

Subjects of the present invention therefore also are the compounds ofFormula (I) and their pharmaceutically acceptable salts for use aspharmaceuticals, their use for activating soluble guanylate cyclase, fornormalizing a disturbed cGMP balance and in particular their use in thetherapy and prophylaxis of the above mentioned syndromes as well astheir use for preparing medicaments for these purposes.

Furthermore, a subject of the present invention is pharmaceuticalcompositions which comprise as active component an effective dose of atleast one compound of Formula (I) and/or a pharmaceutically acceptablesalt thereof and a customary pharmaceutically acceptable carrier, i.e.,one or more pharmaceutically acceptable carrier substances and/oradditives.

Thus, a subject of the invention is, for example, said compound and itspharmaceutically acceptable salts for use as a pharmaceutical,pharmaceutical compositions which comprise as active component aneffective dose of the compound of Formula (I) and/or a pharmaceuticallyacceptable salt thereof and a customary pharmaceutically acceptablecarrier, and the uses of said compound and/or a pharmaceuticallyacceptable salt thereof in the therapy or prophylaxis of theabovementioned syndromes as well as their use for preparing medicamentsfor these purposes.

The pharmaceutical compositions according to the invention can beadministered orally, for example in the form of pills, tablets,lacquered tablets, sugar-coated tablets, granules, hard and soft gelatincapsules, aqueous, alcoholic or oily solutions, syrups, emulsions orsuspensions, or rectally, for example in the form of suppositories.Administration can also be carried out parenterally, for examplesubcutaneously, intramuscularly or intravenously in the form ofsolutions for injection or infusion.

The pharmaceutical compositions can also be administered by the inhaledroute. Dosage forms for inhaled administration may conveniently beformulated as aerosols or dry powders. For compositions suitable and/oradapted for inhaled administration, it is preferred that the compound ofFormula (I) is in a particle-size-reduced form, and more preferably thesize-reduced form is obtained or obtainable by micronisation.

Aerosol formulations, e.g., for inhaled administration, can comprise asolution or fine suspension of the active substance in apharmaceutically acceptable aqueous or non-aqueous solvent. Aerosolformulations can be presented in single or multidose quantities insterile form in a sealed container, which can take the form of acartridge or refill for use with an atomising device or inhaler.Alternatively the sealed container may be a unitary dispensing devicesuch as a single dose nasal inhaler or an aerosol dispenser fitted witha metering valve (metered dose inhaler) which is intended for disposalonce the contents of the container have been exhausted.

Where the dosage form comprises an aerosol dispenser, it preferablycontains a suitable propellant under pressure such as compressed air,carbon dioxide or an organic propellant such as a hydrofluorocarbon(HFC). Suitable HFC propellants include 1,1,1,2,3,3,3-heptafluoropropaneand 1,1,1,2-tetrafluoroethane. The aerosol dosage forms can also takethe form of a pump-atomiser. The pressurised aerosol may contain asolution or a suspension of the active compound. This may require theincorporation of additional excipients e.g., co-solvents and/orsurfactants to improve the dispersion characteristics and homogeneity ofsuspension formulations. Solution formulations may also require theaddition of co-solvents such as ethanol. Other excipient modifiers mayalso be incorporated to improve, for example, the stability and/or tasteand/or fine particle mass characteristics (amount and/or profile) of theformulation.

Pharmaceutical compositions suitable for inhaled administration may alsotake the form of a dry powder inhalable composition. Such a compositioncan comprise a powder base such as lactose, glucose, trehalose, mannitolor starch, the compound of Formula (I) (preferably inparticle-size-reduced form, e.g., in micronised form), and optionally aperformance modifier such as L-leucine or another amino acid, and/ormetals salts of stearic acid such as magnesium or calcium stearate. Insome embodiments, the dry powder inhalable composition comprises a drypowder blend of lactose and the compound of Formula (I) or salt thereof.

Optionally, in particular for dry powder inhalable compositions, apharmaceutical composition for inhaled administration can beincorporated into a plurality of sealed dose containers (e.g.,containing the dry powder composition) mounted longitudinally in a stripor ribbon inside a suitable inhalation device. The container isrupturable or peel-openable on demand and the dose of e.g., the drypowder composition can be administered by inhalation via the device suchas the DISKUS® device (GlaxoSmithKline). Other dry powder inhalers arewell known to those of ordinary skill in the art, and many such devicesare commercially available, with representative devices includingAerolizer® (Novartis), Airmax™ (IVAX), ClickHaler® (Innovata Biomed),Diskhaler® (GlaxoSmithKline), Accuhaler (GlaxoSmithKline), Easyhaler®(Orion Pharma), Eclipse™ (Aventis), FlowCaps® (Hovione), Handihaler®(Boehringer Ingelheim), Pulvinal® (Chiesi), Rotahaler®(GlaxoSmithKline), SkyeHaler™ or Certihaler™ (SkyePharma), Twisthaler(Merck & Co., Inc.), Turbuhaler® (AstraZeneca), Ultrahaler® (Aventis),and the like.

Other suitable administration forms are, for example, percutaneous ortopical administration, for example in the form of ointments, tinctures,sprays or transdermal therapeutic systems, or, for example,microcapsules, implants or rods. The preferred administration formdepends, for example, on the disease to be treated and on its severity.

The amount of active compound of Formula (I) and/or its pharmaceuticallyacceptable salts in the pharmaceutical composition normally is from 0.01to 200 mg, such as from 0.1 to 200 mg, preferably from 1 to 200 mg, perdose, but depending on the type of the pharmaceutical composition it canalso be higher. In some embodiments, the amount of active compound ofFormula (I) and/or its pharmaceutically acceptable salts in thepharmaceutical composition is from 0.01 to 10 mg per dose. Thepharmaceutical compositions usually comprise 0.5 to 90 percent by weightof the compound of Formula (I) and/or their pharmaceutically acceptablesalts. The preparation of the pharmaceutical compositions can be carriedout in a manner known per se. For this purpose, one or more compounds ofFormula (I) and/or their pharmaceutically acceptable salts, togetherwith one or more solid or liquid pharmaceutical carrier substancesand/or additives (or auxiliary substances) and, if desired, incombination with other pharmaceutically active compounds havingtherapeutic or prophylactic action, are brought into a suitableadministration form or dosage form which can then be used as apharmaceutical in human or veterinary medicine.

For the production of pills, tablets, sugar-coated tablets and hardgelatin capsules, it is possible to use, for example, lactose, starch,for example maize starch, or starch derivatives, talc, stearic acid orits salts, etc. Carriers for soft gelatin capsules and suppositoriesare, for example, fats, waxes, semisolid and liquid polyols, natural orhardened oils, etc. Suitable carriers for the preparation of solutions,for example of solutions for injection, or of emulsions or syrups are,for example, water, physiologically acceptable sodium chloride solution,alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar,glucose, mannitol, vegetable oils, etc. It is also possible tolyophilize the compounds of Formula (I) and their pharmaceuticallyacceptable salts and to use the resulting lyophilisates, for example,for preparing preparations for injection or infusion. Suitable carriersfor microcapsules, implants or rods are, for example, copolymers ofglycolic acid and lactic acid.

Besides the active compounds and carriers, the pharmaceuticalcompositions can also contain customary additives, for example fillers,disintegrants, binders, lubricants, wetting agents, stabilizers,emulsifiers, dispersants, preservatives, sweeteners, colorants,flavorings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants.

The dosage of the active compound of Formula (I) and/or of apharmaceutically acceptable salt thereof to be administered depends onthe individual case and is, as is customary, to be adapted to theindividual circumstances to achieve an optimum effect. Thus, it dependson the nature and the severity of the disorder to be treated, and alsoon the sex, age, weight and individual responsiveness of the human oranimal to be treated, on the efficacy and duration of action of thecompounds used, on whether the therapy is acute or chronic orprophylactic, or on whether other active compounds are administered inaddition to compounds of Formula (I). In general, a daily dose ofapproximately 0.0001 to 100 mg/kg, in particular, 0.0001 to 0.30 mg/kgor 0.01 to 0.03 mg/kg (in each case mg per kg of bodyweight) isappropriate for administration to an adult weighing approximately 75 kgin order to obtain the desired results. The daily dose can beadministered in a single dose or, in particular when larger amounts areadministered, be divided into several, for example two, three or fourindividual doses. In some cases, depending on the individual response,it may be necessary to deviate upwards or downwards from the given dailydose. A single daily dose is preferred.

The compounds of Formula (I) activate soluble guanylate cyclase. Due tothis property, apart from use as pharmaceutically active compounds inhuman medicine and veterinary medicine, they can also be employed as ascientific tool or as an aid for biochemical investigations in whichsuch an effect on soluble guanylate cyclase is intended, and also fordiagnostic purposes, for example in the in vitro diagnosis of cellsamples or tissue samples. The compounds of Formula (I) and saltsthereof can furthermore be employed, as already mentioned above, asintermediates for the preparation of other pharmaceutically activecompounds.

One or more additional pharmacologically active agents may beadministered in combination with a compound of Formula (I). Anadditional active agent (or agents) is intended to mean apharmaceutically active agent (or agents) that is active in the body,including pro-drugs that convert to pharmaceutically active form afteradministration, which are different from the compound of Formula (I),and also includes free-acid, free-base and pharmaceutically acceptablesalts of said additional active agents. Generally, any suitableadditional active agent or agents, including but not limited toanti-hypertensive agents, anti-atherosclerotic agents such as a lipidmodifying compound, anti-diabetic agents and/or anti-obesity agents maybe used in any combination with the compound of Formula (I) in a singledosage formulation (a fixed dose drug combination), or may beadministered to the patient in one or more separate dosage formulationswhich allows for concurrent or sequential administration of the activeagents (co-administration of the separate active agents). Examples ofadditional active agents which may be employed include but are notlimited to angiotensin converting enzyme inhibitors (e.g, alacepril,benazepril, captopril, ceronapril, cilazapril, delapril, enalapril,enalaprilat, fosinopril, imidapril, lisinopril, moveltipril,perindopril, quinapril, ramipril, spirapril, temocapril, ortrandolapril), angiotensin II receptor antagonists (e.g., losartan i.e.,COZAAR®, valsartan, candesartan, olmesartan, telmesartan and any ofthese drugs used in combination with hydrochlorothiazide such asHYZAAR®); neutral endopeptidase inhibitors (e.g., thiorphan andphosphoramidon), aldosterone antagonists, aldosterone synthaseinhibitors, renin inhibitors (e.g. urea derivatives of di- andtri-peptides (See U.S. Pat. No. 5,116,835), amino acids and derivatives(U.S. Pat. Nos. 5,095,119 and 5,104,869), amino acid chains linked bynon-peptidic bonds (U.S. Pat. No. 5,114,937), di- and tri-peptidederivatives (U.S. Pat. No. 5,106,835), peptidyl amino diols (U.S. Pat.Nos. 5,063,208 and 4,845,079) and peptidyl beta-aminoacyl aminodiolcarbamates (U.S. Pat. No. 5,089,471); also, a variety of other peptideanalogs as disclosed in the following U.S. Pat. Nos. 5,071,837;5,064,965; 5,063,207; 5,036,054; 5,036,053; 5,034,512 and 4,894,437, andsmall molecule renin inhibitors (including diol sulfonamides andsulfinyls (U.S. Pat. No. 5,098,924), N-morpholino derivatives (U.S. Pat.No. 5,055,466), N-heterocyclic alcohols (U.S. Pat. No. 4,885,292) andpyrolimidazolones (U.S. Pat. No. 5,075,451); also, pepstatin derivatives(U.S. Pat. No. 4,980,283) and fluoro- and chloro-derivatives ofstatone-containing peptides (U.S. Pat. No. 5,066,643), enalkrein, RO42-5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren(2(S),4(S),5(S),7(S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamidhemifumarate) SPP600, SPP630 and SPP635), endothelin receptorantagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalfiland vardenafil), vasodilators, calcium channel blockers (e.g.,amlodipine, nifedipine, veraparmil, diltiazem, gallopamil, niludipine,nimodipins, nicardipine), potassium channel activators (e.g.,nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam),diuretics (e.g., hydrochlorothiazide), sympatholitics, beta-adrenergicblocking drugs (e.g., propranolol, atenolol, bisoprolol, carvedilol,metoprolol, or metoprolol tartate), alpha adrenergic blocking drugs(e.g., doxazosin, prazosin or alpha methyldopa) central alpha adrenergicagonists, peripheral vasodilators (e.g. hydralazine); lipid loweringagents e.g., HMG-CoA reductase inhibitors such as simvastatin andlovastatin which are marketed as ZOCOR® and MEVACOR® in lactone pro-drugform and function as inhibitors after administration, andpharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoAreductase inhibitors such as atorvastatin (particularly the calcium saltsold in LIPITOR®), rosuvastatin (particularly the calcium salt sold inCRESTOR®), pravastatin (particularly the sodium salt sold inPRAVACHOL®), and fluvastatin (particularly the sodium salt sold inLESCOL®); a cholesterol absorption inhibitor such as ezetimibe (ZETIA®)and ezetimibe in combination with any other lipid lowering agents suchas the HMG-CoA reductase inhibitors noted above and particularly withsimvastatin (VYTORIN®) or with atorvastatin calcium; niacin inimmediate-release or controlled release forms, and/or with an HMG-CoAreductase inhibitor; niacin receptor agonists such as acipimox andacifran, as well as niacin receptor partial agonists; metabolic alteringagents including insulin and insulin mimetics (e.g., insulin degludec,insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4)inhibitors (e.g., sitagliptin, alogliptin, omarigliptin, linagliptin,vildagliptin); insulin sensitizers, including (i) PPARy agonists, suchas the glitazones (e.g. pioglitazone, AMG 131, MBX2044, mitoglitazone,lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and otherPPAR ligands, including (1) PPARα/γ dual agonists (e.g., ZYH2, ZYH1,GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, andnaveglitazar); (2) PPARU agonists such as fenofibric acid derivatives(e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate),(3) selective PPARy modulators (SPPARyM's), (e.g., such as thosedisclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409,WO 2004/020408, and WO 2004/066963); and (4) PPARγ partial agonists;(ii) biguanides, such as metformin and its pharmaceutically acceptablesalts, in particular, metformin hydrochloride, and extended-releaseformulations thereof, such as Glumetza™, Fortamet™, and GlucophageXR™;and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g.,ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulindetemir, insulin glulisine, insulin degludec, insulin glargine, insulinlispro and inhalable formulations of each); leptin and leptinderivatives and agonists; amylin and amylin analogs (e.g., pramlintide);sulfonylurea and non-sulfonylurea insulin secretagogues (e.g.,tolbutamide, glyburide, glipizide, glimepiride, mitiglinide,meglitinides, nateglinide and repaglinide); α-glucosidase inhibitors(e.g., acarbose, voglibose and miglitol); glucagon receptor antagonists(e.g., MK-3577, MK-0893, LY-2409021 and KT6-971); incretin mimetics,such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1receptor agonists (e.g., dulaglutide, semaglutide, albiglutide,exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, andBIM-51077, including intranasal, transdermal, and once-weeklyformulations thereof); LDL cholesterol lowering agents such as (i)HMG-CoA reductase inhibitors (e.g., simvastatin, lovastatin,pravastatin, cerivastatin, fluvastatin, atorvastatin, and rosuvastatin),(ii) bile acid sequestering agents (e.g., colestilan, colestimide,colesevalam hydrochloride, colestipol, cholestyramine, anddialkylaminoalkyl derivatives of a cross-linked dextran), (iii)inhibitors of cholesterol absorption, (e.g., ezetimibe), and (iv) acylCoA:cholesterol acyltransferase inhibitors, (e.g., avasimibe);HDL-raising drugs, (e.g., niacin and nicotinic acid receptor agonists,and extended-release versions thereof); antiobesity compounds; agentsintended for use in inflammatory conditions, such as aspirin,non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, andselective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators(GKAs) (e.g., AZD6370); inhibitors of 11β-hydroxysteroid dehydrogenasetype 1, (e.g., such as those disclosed in U.S. Pat. No. 6,730,690, andLY-2523199); CETP inhibitors (e.g., anacetrapib, evacetrapib, andtorcetrapib); inhibitors of fructose 1,6-bisphosphatase, (e.g., such asthose disclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748;6,399,782; and 6,489,476); inhibitors of acetyl CoA carboxylase-1 or 2(ACC1 or ACC2); AMP-activated Protein Kinase (AMPK) activators; otheragonists of the G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119(e.g., MBX2982 and PSN821), and (iii) GPR-40; SSTR3 antagonists (e.g.,such as those disclosed in WO 2009/001836); neuromedin U receptoragonists (e.g., such as those disclosed in WO 2009/042053, including,but not limited to, neuromedin S (NMS)); SCD modulators; GPR-105antagonists (e.g., such as those disclosed in WO 2009/000087); SGLTinhibitors (e.g., ASP1941, SGLT-3, empagliflozin, dapagliflozin,ertugliflozin, canagliflozin, BI-10773, PF-04971729, remogloflozin,TS-071, tofogliflozin, ipragliflozin, and LX-4211); inhibitors of acylcoenzyme A:diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2);inhibitors of fatty acid synthase; inhibitors of acyl coenzymeA:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); agonistsof the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, andM-BAR); ileal bile acid transporter inhibitors; PACAP, PACAP mimetics,and PACAP receptor 3 agonists; PPAR agonists; protein tyrosinephosphatase-1B (PTP-1B) inhibitors; IL-1b antibodies, (e.g., XOMA052 andcanakinumab); and bromocriptine mesylate and rapid-release formulationsthereof; or with other drugs beneficial for the prevention or thetreatment of the above-mentioned diseases including nitroprusside anddiazoxide the free-acid, free-base, and pharmaceutically acceptable saltforms of the above active agents where chemically possible.

The following examples are provided so that the invention might be morefully understood. Unless otherwise indicated, the starting materials arecommercially available. They should not be construed as limiting theinvention in any way.

Several methods for preparing the compounds of this invention aredescribed in the following Schemes and Examples. Starting materials andintermediates are purchased, made from known procedures, or as otherwiseillustrated. Some frequently applied routes to the compounds of Formula(I) are also described by the Schemes as follows. In some cases theorder of carrying out the steps of reaction schemes may be varied tofacilitate the reaction or to avoid unwanted reaction products. The “R”and “X” groups in the Schemes correspond to the variables defined inFormula (I) at the same positions on the structures.

Scheme 1 outlines the general approach to assembling compounds of typeS-1d. Starting with an amidine S-1a and coupling with eithermalononitrile S-1b or lactam S-1c, in the presence of either aninorganic base (e.g., KHCO₃) or amine base (e.g., NEt₃) respectively,affords pyrimidine containing substrates S-1d.

Malononitrile type coupling partners can be assembled as outlined inScheme 2, lines A and B. Intermediate S-2a can either be purchased(R⁴=Me), or can be generated in one-step from diethyl oxalate throughtreatment with a Grignard reagent or other organometallic reagents.Condensation of malononitrile with intermediate S-2a, analogous toliterature conditions (Hagiwara et. al. Synthesis 1974, 9, 669) affordsintermediate S-2b. Subsequent 1,4-addition with a Grignard reagent orlithiate in a solvent such as THF at room temperature to −78° C. affordsfunctionalized malononitrile S-1b. An alternate approach to derivatizedmalononitriles, in which the R⁴ group is introduced later, is outlinedin line B. Starting with a di-alkyl oxalate, condensation withmalononitrile analogous to conditions described in the literature(Sentman et. al. J. Org. Chem. 1982, 47, 4577) affords intermediateS-2d. Subsequent treatment with an Grignard reagent affords intermediateS-2e, analogous to intermediate S-1b when R³=CO₂R¹⁰

An alternative method for assembling malononitrile type reagents isoutlined below in Scheme 3. Functionalized esters S-3a can either bepurchased or assembled via copper catalyzed cross-coupling reactionsfollowed by decarboxylation as outlined in line B of Scheme 3. S-3a mayalso be prepared from the corresponding carboxylic acid by treatmentwith trimethylsilyl diazomethane or methanol with catalytic sulfuricacid. S-3a may be prepared by the alpha arylation/heteroarylation ofesters as described by Buchwald, S. L. et al Organic Letters 2009,11(8), 1773; or by Shen, H. C. et al Organic Letters 2006, 8(7), 1447.Additional functionalization of S-3a via alkylation in the presence of abase such as LiHMDS, NaHMDS, NaH or LDA in a solvent such as THF or DMFaffords intermediate S-3b. The compound S-3c is prepared by treatingcompound S-3b with a brominating reagent such as NBS and AIBN in asolvent such as carbon tetrachloride at refluxing temperatures.Alternatively, the compound S-3c may be prepared by reaction with NBSand magnesium perchlorate in acetonitrile solvent at room temperature asdescribed by Yang, D. et al Journal of Organic Chemistry 2002, 67(21),7429. Compound S-3c may also be prepared by treating compound S-3b witha base such as sodium hydride followed by treatment with NBS. CompoundS-1b is obtained from S-3c by reaction with malononitrile and a basesuch as sodium hydride, t-BuOK, K₂CO₃ or DBU in a solvent such as THF orDMF at ambient temperature to elevated temperatures.

Malononitriles of type S-1b can be cyclized in the presence of alkoxidetype bases such as sodium methoxide in methanol or sodium ethoxide inethanol to form lactams S-1c as shown in Scheme 4. Additionally,functionalized alkyne containing malononitrile S-4a can undergo1,3-dipolar cycloaddition with functionalized carbon-linked azides inthe presence of a copper reagent to afford 1,2,3-triazoles S-4b.

Heterocycles of type S-5e and S-5h can be generated as outlined inScheme 5, lines A and B. S-5e can be prepared as outlined in line Astarting from commercially available ethyl 2-cyanopropanoate S-5a, inwhich treatment with chlorotrimethyl silane in water affords amide S-5b.Subsequent cyclization with a functionalized α-bromoketone reagent suchas S-5c in the presence of silver triflate leads to S-5d. From here,bromination with NBS and LiHMDS, followed by treatment withmalononitrile, affords target substrates such as S-5e. S-5h can beaccessed as outlined in line B, starting from commercially availablethioamide S-5f. Treatment with α-bromoketones such as S-5c, followed bybromination with KBr and hydrogen peroxide and followed lastly bytreatment with malononitrile affords substrates of type S-5h.

The general approach to amidines S-1a is outlined in Scheme 6 below.Starting with generic type 2-fluorobenzaldehyde S-6a, condensation withhydrazine while heating in a solvent such as DMA affords the indazoleS-6b. Subsequent iodination with an iodination reagent such as NIS in asolvent such as DCM or DMA, followed by palladium catalyzed crosscoupling with zinc cyanide using a catalyst such as Pd₂(dba)₃ and DPPFin a solvent such as DMA affords the nitrile intermediate S-6d.Alkylation of the indazole with bromo or iodo halide using a base suchas cesium carbonate, sodium hydride or K₂CO₃ in a solvent such as DMF,DMA or acetonitrile at ambient temperature to 100° C. gives S-6e.Conversion of the nitrile to amidines of type S-1a can be accomplishedwith a reagent such as amino(chloro)methylaluminum, prepared fromtrimethylaluminum and ammonium chloride, in a non-polar solvent such astoluene while heating as described by Garigipati, R. S. et al.Tetrahedron Letters 1990, 31(14), 1969. Alternative conditions utilizesodium methoxide followed by treatment with ammonium chloride in thepresence of acetic acid.

As described in Scheme 7, aza-indazole substrates S-7a can be furtherfunctionalized by oxidation of the pyridine with mCPBA in acetic acidsolvent to afford the N-oxide, followed by treatment with POCl₃ toafford the alpha-chloro substituted intermediate S-7c that can besubsequently converted to amidine S-7d.

Some common routes for final compound synthesis are outlined in theSchemes 8, 9 and 10 below. One approach as generically outlined inScheme 8, is coupling of functionalized malononitrile S-8c or lactamS-8b with amidines to afford intermediates of type S-8d bearing anester. Amidine coupling with malonontrile reagents of type S-8c,typically are performed in an alcohol solvent such as tBuOH at RT to 80°C. and utilize a base such as KHCO₃, though reactions can also be run inthe absence of base. Amidine couplings with activated lactam structuressuch as S-8b are typically ran in solvents such as THF at roomtemperature to 80° C. with an alkyl amine base such as Et₃N. Subsequenthydrolysis with a base such as lithium hydroxide in a solvent mixturecontaining a polar organic solvent such as dioxane or acetonitrile incombination with water affords final products S-8e. Chiral resolution ofenantiomers can occur at any of the stages up to and including posthydrolysis formation of S-8e. This resolution includes chiral resolutionof functionalized malonitriles S-8c or lactams S-8b or post condensationwith amidines at the ester intermediate S-8d or post hydrolysisresolution of acid S-8e.

Another method for the synthesis of functionalized acids linked tothiazoles is outlined in Scheme 9. Starting from either chiral orracemic S-9a (assembled as generally outlined in Scheme 1), conversionto the amide with ammonia in methanol, followed by treatment withLawesson's reagent in toluene at elevated temperatures affords thioamideintermediate S-9b. Coupling with bromo-functionalized β-keto esters inan alcohol such as ethanol at elevated temperatures followed byhydrolysis affords acid S-9c. In addition to generating chiral S-9athrough use of chiral reagents of type S-1c or resolution of ester S-9a,chiral resolution can occur at thioamide S-9b or the subsequent ester oracid S-9c.

Additionally, compounds of type S-10b can be formed from the more activesingle enantiomers of type S-8e (general synthesis outlined in Scheme 8)using common coupling reagents such asO-(benzotriazol-1-yl)-N,N,N′,N-tetramethyluronium tetrafluoroborate tocouple with amino-esters. The ester intermediate S-10a can then behydrolyzed to provide S-10b.

Compounds of type S-11b can be formed from type S-8e (general synthesisoutlined in Scheme 8). The nitrile compounds type S-11a can be formed byconversion of the carboxylic acid to the corresponding amide usingreagent such as Boc anhydride and TFA, followed by dehydration of theamide to form the nitrile with reagents such as trifluoroaceticanhydride. Treatment of compounds of type S-1a with sodium azide orTMS-azide provides tetrazole compounds type S-11b.

Compounds of the present invention possess an asymmetric center at thecarbon bearing the R³ and R⁴ substituents which can be either R or Sconfiguration. These enantiomeric mixtures may be separated or resolvedto single enantiomers using chiral SFC chromatography. Racemic materialcan be resolved to enantiomerically pure compounds at the final step, orone of the earlier steps in the route as outlined in Schemes 8, 9 and10. For example, intermediates S-1b and S-1c can undergo chiralresolution to afford enantiopure isomers that may be carried on in thecoupling with amidines to enantiomerically pure compounds.Alternatively, enantiomeric resolution can be performed post formationof general intermediate S-1d. For example, chiral resolution ofintermediates of the type S-8d, S-9b, or S-10a to single enantiomers maybe further elaborated to enantiopure compounds or may be resolved atfinal compounds of type S-8e, S-9c, S-10b. Unless otherwise noted, theexamples in the present invention are enantiomerically pure isomers (Ror S). Biochemical assay data is listed for the more active enantiomerif only one of the enantiomers is active.

The independent synthesis of diastereomers and enantiomers or theirchromatographic separations may be achieved using methods familiar tothose skilled in the art and by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by X-ray crystallography of crystalline products orcrystalline intermediates which are derivatized, if necessary, with areagent containing an asymmetric center of known absolutestereochemistry, or by vibrational circular dichroism (VCD)spectroscopy.

Throughout the synthetic schemes and examples, abbreviations andacronyms may be used with the following meanings unless otherwiseindicated: AIBN=2,2′-azobisisobutyronitrile; Anhydr.=Anhydrous;Aq.=aqueous; atm=atmosphere; bp, b.p.=boiling point; br s=broad singlet;Bu=butyl; t-Bu=tert-butyl; BuLi=butyllithium; t-BuOH,tert-BuOH=tert-butanol; tBuOK=potassium tert-butoxide; CDCl₃=deuteratedchloroform; CD₃OD=Tetradeuteromethanol; CELITE=diatomaceous earth;CF₃=trifluoromethyl; cGMP=cyclic guanosine monophosphate; conc,conc.=concentrated, concentrate, concentrates;DBU=1,8-Diazabicyclo[4.3.0]undec-7-ene; DCM=dichloromethane; 1,2-DCE,DCE=1,2-dichloroethane; DETA-NO=Diethylenetriamine/nitric oxide adduct;DMA, DMAC=N,N-dimethylacetamide; DMF=N,N-dimethylformamide;DMSO=dimethylsulfoxide; dppf=1,1′-bis(diphenylphosphino)ferrocene;DTT=dithiothreitol; EAB=egg albumin; EBSS=Earle's balanced saltsolution; equiv, eq.=equivalent(s); Et=ethyl; Et₃N=triethylamine;EtOAc=ethyl acetate; EtOH=ethanol; GTP=guanosine triphosphate; h,hr=hour; HPLC=High pressure liquid chromatography; Int.=intermediate;iPr=isopropyl; IPA, IP=inflection points; i-PrOH=Isopropanol;IT=intra-tracheal; LCMS, LC/MS=liquid chromatography-mass spectrometry;LDA=lithium diisopropylamide; LiHMDS, LHMDS=lithiumbis(trimethylsilyl)amide; min, min.=minute; M=Molar; Me=methyl; MeCN,ACN=acetonitrile; Mel=methyl iodide; MeOH=methanol; mp, m.p.=meltingpoint; mpk=milligrams per kilogram; N=Normal; N₂=nitrogen; NaOMe=sodiummethoxide; NCS=N-chloro succinimide; NBS=N-bromo succinimide;NaHMDS=sodium bis(trimethylsilyl)amide; NMR=nuclear magnetic resonance;N.D.=not determined; NIS=N-iodo succinimide; PDA=photodiode array;Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium (0); Ph=phenyl;Pr=propyl; psig=pounds per square inch gauge; PTLC, prep TLC=preparativethin layer chromatography; rac=racemic; rt=retention time;RP-HPLC=reverse phase HPLC; RT=room temperature; sat., sat'd=saturated;SFC=supercritical fluid chromatography; sGC=soluble guanylate cyclase;TFA=trifluoroacetic acid; TFAA=trifluoroacetic anhydride; TLC=thin layerchromatography; THF=tetrahydrofuran; TMS=trimethylsilyl; VCD=vibrationalcircular dichroism; v, v/v=volume, volume to volume; w, w/w=weight,weight to weight.

Columns used in the chiral resolution of stereoisomers are set forth inthe examples below as follows: AD=CHIRALPAK® AD; AD-H=CHIRALPAK® AD-H;AS=CHIRALPAK® AS; AS-H=CHIRALPAK® AS-H; IA=CHIRALPAK® IA; IC=CHIRALPAK®IC; OD-H=CHIRALCEL® OD-H; and OJ-H=CHIRALCEL® OJ-H.

The following examples are provided to more fully illustrate the presentinvention, and shall not be construed as limiting the scope in anymanner. Unless stated otherwise, the following conditions were employed.All operations were carried out at room or ambient temperature (RT),that is, at a temperature in the range 18-25° C. Reactions are generallydone using commercially available anhydrous solvents under an inertatmosphere, either nitrogen or argon. Microwave reactions were doneusing a BIOTAGE Initiator™ or CEM EXPLORER® system. Evaporation ofsolvent was carried out using a rotary evaporator under reduced pressure(4.5-30 mmHg) with a bath temperature of up to 50° C. The course ofreactions was followed by thin layer chromatography (TLC) and/or tandemhigh performance liquid chromatography (HPLC) followed by electron spraymass spectroscopy (MS), herein termed LCMS, and any reaction times aregiven for illustration only. The structure of all final compounds wasassured by at least one of the following techniques: MS or protonnuclear magnetic resonance (¹H NMR) spectrometry, and the purity wasassured by at least one of the following techniques: TLC or HPLC. ¹H NMRspectra were recorded on either a Varian Unity or a Varian Inovainstrument at 300, 400, 500 or 600 MHz using the indicated solvent. Whenline-listed, NMR data are in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative toresidual solvent peaks (multiplicity and number of hydrogens).Conventional abbreviations used for signal shape are: s. singlet; d.doublet (apparent); t. triplet (apparent); m. multiplet; br. broad; etc.MS data were recorded on a Waters Micromass or WatersZQ unit, interfacedwith a Hewlett-Packard (AGILENT 1100) HPLC instrument, and operating onMASSLYNX/OpenLynx software. Electrospray ionization was used withpositive (ES+) or negative ion (ES−) detection; and diode arraydetection. Purification of compounds by preparative reverse phase HPLCwas performed on a GILSON system using a YMC-Pack Pro C18 column (150×20mm i.d.) eluting at 20 mL/min with a water/acetonitrile (0.1% TFA)gradient (typically 5% acetonitrile to 95% acetonitrile) or using aSUNFIRE Prep C18 OBD 5 μM column (100×30 mm i.d.) eluting at 50 mL/minwith a water/acetonitrile (0.1% TFA) gradient. Purification of compoundsby preparative mass triggered reverse phase HPLC was performed on WatersMS directed Preparative Scale HPLC. Purification of compounds bypreparative thin layer chromatography (PTLC) was conducted on 20×20 cmglass plates coated with silica gel, commercially available fromAnaltech; or E. Merck. Flash column chromatography was carried out on aglass silica gel column using Kieselgel 60, 0.063-0.200 mm (SiO₂), or ona BIOTAGE SiO₂ cartridge system using the BIOTAGE Horizon and BIOTAGESP-1 systems; or a Teledyne Isco SiO₂ cartridge using the COMBIFLASH Rfsystem. Chemical symbols have their usual meanings, and the followingabbreviations have also been used: h or hr (hours), min (minutes), v(volume), w (weight), b.p. (boiling point), m.p. (melting point), L(litre(s)), mL (millilitres), g (gram(s)), mg (milligrams(s)), mol(moles), mmol (millimoles), eq or equiv (equivalent(s)), μM(micromolar), nM (nanomolar), ca (circa/about).

The following are representative procedures for the preparation ofintermediates used to prepare the final products described in theExamples that follow thereafter. These examples are provided for thepurpose of further illustration only and are not intended to belimitations on the disclosed invention.

It is understood that a chiral center in a compound may exist in the “S”or “R” stereo-configurations, or as a mixture of both. In some of theexamples for intermediate compounds and final compounds, such compoundshaving a racemic chiral center were separated into individualstereoisomers, for example, referred to as isomer A (or enantiomer A orthe like), which refers to the observed faster eluting isomer, andisomer B (or enantiomer B or the like), which refers to the observedslower eluting isomer, and each such isomer may be noted in the exampleas either the fast or slow eluting isomer. When a single “A” or “B”isomer intermediate is used to prepare a downstream compound, thedownstream compound may take the “A” or “B” designation that correspondsto the previously used intermediate.

Any intermediates described below may be referred to herein by theirnumber preceded by “I-.” For illustration, the racemic parent titlecompound would be referred to as Intermediate 37 (I-37, or rac I-37),and the separated stereoisomers are noted as Intermediates 37A and 37B(or I-37A and I-37B). In some examples, compounds having a chiral centerwere derived synthetically from a single isomer intermediate; e.g.,Example 13B—was made using stereoisomer I-11B. In some casesintermediates or examples contain more than one chiral center. In suchcases, the separation of isomers may require more than one chiralseparation. In such cases, the intermediate or example number can befollowed by 2 letters (e.g. I-38AB or Ex-5BA). For these intermediatesand examples, the first letter represents the A or B isomer from thefirst separation and the second letter represents the A or B isomer fromthe second separation. Absolute stereochemistry of separatestereoisomers in the Examples and Intermediates was not determinedunless stated otherwise in an Example or Intermediate synthesis. Anasterisk (*) may be used in a chemical structure drawing that indicatesthe location of a chiral center.

Intermediate 1 Methyl 3-(4-iodophenyl)-2-methylpropanoate

To a flask under an inert atmosphere of nitrogen, containing a solutionof methyl 3-(4-iodophenyl)propanoate (2 g, 6.89 mmol) in 27 mL THF at−78° C. was slowly added a solution of potassiumbis(trimethylsilyl)amide (1 M in THF, 8.3 mL, 8.3 mmol). The resultingsolution was stirred 30 min at −78° C. before methyl iodide (0.560 mL,8.96 mmol) was added. The reaction was stirred 2 h at −78° C. thenquenched with a 1 M aq. solution of hydrochloric acid. The mixture wasextracted with EtOAc (3×). The organic layer was washed with brine,dried over anhydr. MgSO₄, filtered and concentrated in vacuo to dryness.The residue was purified by silica gel chromatography using anEtOAc:hexane gradient to afford the racemic title product I-1. ¹H NMR(500 MHz, CDCl₃) δ 7.66-7.60 (m, 2H), 6.94 (d, J=8.2 Hz, 2H), 3.67 (s,3H), 2.99 (dd, J=13.5, 7.1 Hz, 1H), 2.73 (h, J=7.0 Hz, 1H), 2.64 (dd,J=13.4, 7.4 Hz, 1H), 1.18 (d, J=6.9 Hz, 3H); m/z 305 (M+1).

Intermediate 2 Methyl 3-(4-iodophenyl)-2,2-dimethylpropanoate

To a flask under an inert atmosphere of nitrogen, containing a solutionof methyl isobutyrate (1.16 mL, 10.1 mmol) in THF (34 mL) at −78° C. wasslowly added a solution of lithium diisopropylamide (1 M in THF, 11.1mL, 11.1 mmol). The resulting solution was stirred 1 h at −78° C. beforea solution of 4-iodobenzyl bromide (3 g, 10.10 mmol) in THF (2 mL) wasadded. The reaction was allowed to warm up to RT and stirred 2 h, thenquenched by the addition of sat. aq. NH₄Cl. The mixture was extractedwith EtOAc (3×). The organic layer was washed with brine, dried overanhydr. MgSO₄, filtered and concentrated in vacuo to dryness. Theresidue was purified by silica gel chromatography using an EtOAc:hexanegradient to afford the racemic title product I-2. ¹H NMR (500 MHz,CDCl₃) δ 7.65-7.54 (m, 2H), 6.94-6.81 (m, 2H), 3.68 (s, 3H), 2.82 (s,2H), 1.20 (s, 6H); m/z=319 (M+1).

Intermediate 3 Ethyl 3-(3-iodophenyl)-2,2-dimethylpropanoate

The title compound I-3 was prepared using essentially the sameprocedures described for intermediate 2 using 3-iodobenzyl bromide andethyl isobutyrate as starting material. m/z=333 (M+1)

Intermediate 4 Tert-butyl 3-(6-bromopyridin-3-yl)-2,2-dimethylpropanoate

The title compound I-4 was prepared using essentially the sameprocedures described for intermediate 2 using2-bromo-5-(bromomethyl)pyridine and t-butyl isobutyrate as startingmaterial. m/z=316 (M+1)

Intermediate 5 Methyl 3-(2-bromo-4-iodophenyl)propanoate

Step A—3-(2-bromo-4-nitrophenyl)propanoic acid

To a flask containing 3-(4-nitrophenyl)propanoic acid (8 g, 41.0 mmol)in water (40 mL) and concentrated sulfuric acid (40 mL) at 0° C. wasslowly added N-bromosuccinimide (9.48 g, 53.3 mmol). The resultingmixture was stirred in the dark for 2 h at 40° C., then diluted withwater and extracted with EtOAc (3×). The organic layer was washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo to dryness to afford the title compound.

Step B—methyl 3-(2-bromo-4-nitrophenyl)propanoate

Into a flask were placed 3-(2-bromo-4-nitrophenyl)propanoic acid (16 g,40.9 mmol) concentrated sulfuric acid (20 mL) and MeOH (40 mL). Theresulting mixture was stirred for 2 h at 80° C. then cooled to RT,diluted with water and extracted with EtOAc (3×). The organic layer waswashed with brine, dried over anhydr. Na₂SO₄, and filtered. The filtratewas concentrated in vacuo and the residue was purified by silica gelcolumn chromatography with EtOAc:petroleum ether (0-30%) to afford thetitle compound.

Step C—methyl 3-(4-amino-2-bromophenyl)propanoate

Into a flask were placed methyl 3-(2-bromo-4-nitrophenyl)propanoate(10.0 g, 24.3 mmol), iron (5.4 g, 97 mmol) and ammonium chloride (3.9 g,72.9 mmol) in a mixture of ethanol (80 mL) and water (20 mL). Theresulting mixture was stirred for 1 h at 90° C. The solid was filteredout, and washed with EtOAc. The organic layer was washed with brine,dried over anhydr. Na₂SO₄, and filtered. The filtrate was concentratedin vacuo and the residue was dissolved in water, the pH of the solutionwas adjusted to pH 1 with hydrochloric acid (1 N). The resultingsolution was extracted with EtOAc (2×). The pH adjusted to 10 withsodium hydroxide (1 N). The resulting solution was extracted with EtOAc(3×) and the organic layer combined, dried over anhydr. Na₂SO₄, filteredand the filtrate was concentrated in vacuo to dryness to afford thetitle compound.

Step D-methyl 3-(2-bromo-4-iodophenyl)propanoate

To a flask containing methyl 3-(4-amino-2-bromophenyl)propanoate (5.0 g,19.4 mmol), concentrated hydrochloric acid (15 mL) and water (13 mL) at0° C. was added dropwise a solution of sodium nitrite (1.47 g, 21.3mmol) in water (2 mL). The mixture was stirred for 1 h at 0° C. beforepotassium iodide (6.43 g, 38.7 mmol) was added. After an additional 5min at 0° C. the mixture was diluted with Et₂O and washed with of aq.sat. NaHSO₄. The organic layer was dried over anhydr. MgSO₄, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography with EtOAc:petroleum ether(0-30%) to afford the title compound I-5. ¹H NMR (300 MHz, CDCl₃) δ 7.85(d, J=1.8 Hz, 1H), 7.51 (dd, J=1.8, 8.4 Hz, 1H), 6.97 (d, J=8.4 Hz, 1H),3.65 (s, 3H), 2.98 (t, J=7.5 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H).

Intermediate 6 Methyl 3-(4-iodo-2-methoxyphenyl)propanoate

Step A—7-iodochroman-2-one

Into a flask were placed 3-(4-iodophenyl)propanoic acid (6.0 g, 21.7mmol), trifluoroacetic acid (109 mL) and[bis(trifluoroacetoxy)iodo]benzene (14.0 g, 32.6 mmol). The mixture wascooled to 0° C. and of boron trifluoride etherate (4.1 mL, 32.6 mmol)was added dropwise. The resulting mixture was stirred for 16 h at RT.The reaction was quenched by the addition of aq. sat. NaHCO₂, extractedwith EtOAc (3×). The organic layer was washed with brine, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo.and the residue was purified by silica gel column chromatography withEtOAc:petroleum ether (0-30%) to afford the title compound.

Step B—3-(2-hydroxy-4-iodophenyl)propanoic acid

Into a flask containing 7-iodochroman-2-one (2.8 g, 10.2 mmol) in a THF(20 mL) water (20 mL) mixture was added LiOH (2.1 g, 51.1 mmol). Theresulting mixture was stirred for 16 h at RT. The reaction was quenchedby the addition of aq. solution of hydrochloric acid (2 N) extractedwith EtOAc (3×). The organic layer was washed with brine, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo todryness to afford the title compound.

Step C—methyl 3-(4-iodo-2-methoxyphenyl)propanoate

Into a flask containing 3-(2-hydroxy-4-iodophenyl)propanoic acid (3.0 g,10.3 mmol) and iodomethane (1.9 mL, 30.8 mmol) in DMF (50 mL) was addedpotassium carbonate (5.7 g, 41.1 mmol). The resulting mixture wasstirred for 16 h at 50° C. The reaction was quenched by the addition ofwater extracted with EtOAc (3×). The organic layer was washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:petroleum ether (0-30%) to afford the titlecompound I-6. ¹H NMR (300 MHz, CDCl₃): δ 7.49 (dd, J=8.7 Hz, 2.4 Hz,1H), 7.44 (d, J=2.4 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 3.81 (s, 3H), 3.69(s, 3H), 2.88 (t, J=7.5 Hz, 2H), 2.59 (t, J=7.5 Hz, 2H).

Intermediate 7 Methyl 5-bromo-2,2-dimethyl-4-oxopentanoate

To a flask containing methyl 4-chloro-2,2-dimethylpent-4-enoate (19.0mL, 113 mmol) in a ethanol (100 mL) water (75 mL) mixture at 0° C. wasadded dropwise bromine (5.95 mL, 115 mmol) and the reaction was stirred3 h at 0° C. The reaction was diluted with water extracted with DCM(3×). The organic layers were combined washed with aq. sat. NaHCO₃ (2×)and Brine (1×), dried over anhydr. MgSO₄, and filtered. The filtrate wasconcentrated in vacuo to dryness to afford the title compound I-7. ¹HNMR (500 MHz, CDCl₃): δ 3.86 (s, 2H); 3.67 (s, 3H); 2.93 (s, 2H); 1.26(s, 6H).

Intermediate 8 Trans-ethyl 2-(2-bromoacetyl)cyclopropane-1-carboxylate

To a flask containing trans-ethyl 2-acetylcyclopropanecarboxylate (700mg, 4.48 mmol) in ethanol (14 mL) at 0° C. was added dropwise bromine(0.28 mL, 5.38 mmol). The resulting mixture was stirred for 3 h at 0° C.and 16 h at RT. The reaction solution was quenched by the addition ofwater, extracted with DCM. The organic layers combined, washed with aq.sat. NaHCO₃ and brine, dried over anhydr. MgSO₄, and filtered. Thefiltrate was concentrated in vacuo to dryness to afford the titleproduct. ¹H NMR (300 MHz, CDCl₃) δ 4.22-4.09 (m, 2H), 4.05 (s, 2H),2.75-2.68 (m, 1H), 2.29-2.23 (m, 1H), 1.59-1.48 (m, 2H), 1.32-1.26 (m,3H).

Intermediate 9 Methyl 1-(3-bromo-2-oxopropyl)cyclopropane-1-carboxylate

Step A—tert-butyl 1-(2-(bromomethyl)allyl)cyclopropane-1-carboxylate

To a flask, under an inert atmosphere of nitrogen, containingdiisopropylamine (8.90 g, 88 mmol) in THF (75 mL) at −78° C. was addeddropwise n-butyllithium (32.3 mL, 81 mmol, 2.5M in THF). The resultingmixture was slowly warmed to RT and stirred for 30 min at RT then coolback down to −78° C. tert-butyl cyclopropanecarboxylate (10 g, 70.3mmol) was added dropwise and the resulting mixture was stirred for 3 hat −78° C. before 2,3-dibromoprop-1-ene (15.5 g, 77 mmol) was addeddropwise. The resulting mixture was slowly warmed up to RT and stirredfor 16 h at RT. The reaction was quenched by the addition of aq. sat.NH₄Cl, extracted with EtOAc (3×). The organic layers were combined,dried over anhydr. Na₂SO₄, and filtered. The filtrate was concentratedin vacuo. The residue was purified by silica gel column chromatographywith EtOAc:petroleum ether (0-10%) to afford the title compound.

Step B—1-(3-bromo-2-oxopropyl)cyclopropane-1-carboxylic acid

To a flask containing tert-butyl1-(2-(bromomethyl)allyl)cyclopropane-1-carboxylate (1.0 g, 3.83 mmol) ina ethanol (5 mL), and water (4 mL) mixture at 0° C. was added bromine(673 mg, 4.21 mmol). The resulting mixture was stirred for 4 h at RTthen concentrated in vacuo to afford the crude title material that wasused directly in step C.

Step C—methyl 1-(3-bromo-2-oxopropyl)cyclopropane-1-carboxylate

To a flask containing crude1-(3-bromo-2-oxopropyl)cyclopropane-1-carboxylic acid (assumed 3.83mmol) in MeOH (10 mL) was added sulfuric acid (0.5 mL, 9.38 mmol) andthe resulting mixture was stirred for 2 h at reflux. The reactionmixture was cooled to RT, diluted with EtOAc washed with aq. sat. NaHCO₃(2×) and brine, dried over anhydr. Na₂SO₄, and filtered. The filtratewas concentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:petroleum ether (5-15%) to afford I-9. ¹H NMR(400 MHz, CDCl₃) δ 4.00 (s, 2H), 3.66 (s, 3H), 2.86 (s, 2H), 1.45-1.35(m, 2H), 0.93-0.84 (m, 2H).

Intermediate 10, 10A and 10BEthyl-2-(dicyanomethyl))-2-methylbut-3-ynoate and the S and R IsomersThereof

To a flask containing anhydr. LiCl (25.8 mg, 0.609 mmol) in THF (1 mL),was added a solution of ethynylmagnesium bromide (1.3 mL, 0.64 mmol,0.5M in THF). The reaction was stirred at RT for 0.5 h. The resultingsolution was then quickly added dropwise via syringe to a solution ofethyl 3,3-dicyano-2-methylprop-2-enoate (0.609 mL, 0.609 mmol, 1Msolution in benzene) (prepared according to Hagiware et. al. Synthesis1974, 9, 669) in THF (22.5 mL) at −10° C. The reaction was stirred for10 min then quenched with sat. aq. NH₄Cl and diluted with water andEtOAc. The layers were separated and the organic layer was dried overanhydr. Na₂SO₄, and concentrated in vacuo to dryness. The residue waspurified by silica gel chromatography using an EtOAc:hexanes gradient toafford the racemic title product I-10. The racemic material was resolvedusing chiral SFC (OJ-H column) to afford isomers I-10A (faster eluting)and I-10B (slower eluting). ¹H NMR (500 MHz, CDCl₃): δ 4.34 (2H, q,J=7.2 Hz), 4.31 (1H, s), 2.66 (1H, s), 1.80 (3H, s), 1.35 (3H, t, J=7.1Hz).

Intermediate 11, 11A and 11B Ethyl3,3-dicyano-2-(4-(3-methoxy-3-oxopropyl)phenyl)-2-methylpropanoate andthe S and R Isomers Thereof

To a flask under an inert atmosphre of nitrogen, containing a solutionof methyl 3-(4-iodophenyl)propanoate (1.3 g, 4.48 mmol) in THF (6 mL) at−40° C. was slowly added isopropylmagnesium chloride lithium chloridecomplex (3.9 mL, 5.18 mmol, 1.3 M in THF). The resulting solution wasstirred 1 h at −30° C. then cooled −50° C. Ethyl3,3-dicyano-2-methylprop-2-enoate (3.0 mL, 3.05 mmol, 1 M in benzene)(prepared according to Hagiware et. al. Synthesis 1974, 9, 669) wasslowly added and the reaction was stirred for 1 h at −50° C., thenquenched with sat. aq. NH₄Cl and diluted with water and EtOAc. Thelayers were separated and the organic layer was dried over anhydr.Na₂SO₄, and concentrated in vacuo to dryness. The residue was purifiedby silica gel chromatography using an EtOAc/petroleum ether (0%-30%)gradient to afford the racemic title product I-11. The racemic materialwas resolved using Chiral SFC (CHIRALPAK® AD) to afford isomers I-11A(faster eluting) and I-11B (slower eluting). ¹H NMR (400 MHz, CDCl₃) δ7.32-7.19 (m, 4H), 4.45 (s, 1H), 4.36-4.14 (m, 2H), 3.67 (s, 3H), 2.96(t, J=7.8 Hz, 2H), 2.64 (dd, J=8.4, 7.2 Hz, 2H), 1.97 (s, 3H), 1.25 (t,J=7.1 Hz, 3H); m/z=329 (M+1).

Using a similar procedure described for the synthesis of intermediate 10or 11, the following compounds in Table 1 were prepared using fromcommercial starting reagents or compounds known in the literature.

TABLE 1

Chiral Resolution Int. Column R³ m/z (M + 1) 12 —

343 13A 13B IA

357 14 —

407 15A 15B AS

329 16 —

371 17 —

357 (M − 1) 18 —

¹H NMR (400 MHz, CDCl₃) δ 8.13-8.03 (m, 2H), 7.62-7.50 (m, 2H), 4.54 (s,1H), 4.36-4.20 (m, 2H), 3.94 (s, 3H), 2.04 (s, 3H), 1.25 (t, J = 7.1 Hz,3H). 19 —

324 20 —

400

Intermediate 21, 21A and 21B Ethyl2-(4-bromophenyl)-3,3-dicyano-2-methylpropanoate and the S and R IsomersThereof

Step A—ethyl 2-(4-bromophenyl)propanoate

To a flask containing ethyl 2-(4-bromophenyl)acetate (20.0 g, 82.9 mmol)in THF (200 mL) at 0° C. was added dropwise a solution of lithiumbis(trimethylsilyl) amide (99.6 mL, 99.6 mmol, 1M in THF). The resultingsolution was stirred for 1 h at 0° C. then iodomethane (11.7 g, 82.4mmol) was added dropwise at 0° C. The reaction mixture was allowed towarm up to RT for 2 h and quenched by the addition of sat. aq. NH₄Cl.The resulting solution was extracted with EtOAc (3×) and the organiclayers were combined, dried over anhydr. Na₂SO₄ filtered and thefiltrate was concentrated in vacuo to dryness. The residue was purifiedby silica gel chromatography using EtOAc:petroleum ether to afford thetitle compound.

Step B—Ethyl 2-bromo-2-(4-bromophenyl)propanoate

Into a flask were placed ethyl 2-(4-bromophenyl)propanoate (19.5 g, 75.8mmol), 2,2′-azobisisobutyronitrile (1.25 g, 7.61 mmol) andN-bromosuccinimide (16 g, 89.9 mmol) in tetrachloromethane (100 mL). Theresulting solution was stirred for 3 h at 80° C. then quenched by theaddition of sat. aq. sodium thiosulfatepentahydrate. The resultingsolution was extracted with EtOAc (3×) and the organic layers werecombined, dried over anhydr. Na₂SO₄ filtered and the filtrate wasconcentrated in vacuo to dryness. The residue was purified by silica gelchromatography using EtOAc: petroleum ether to afford the titlecompound.

Step C—Ethyl 2-(4-bromophenyl)-3,3-dicyano-2-methylpropanoate

Into a flask containing sodium hydride (1.5 g, 62.5 mmol) in DMF (200mL) at 0° C. was added in portions propanedinitrile (2.4 g, 36.3 mmol).The resulting solution was stirred for 30 min at 0° C. before ethyl2-bromo-2-(4-bromophenyl) propanoate (10.0 g, 29.8 mmol) was added inportions. The resulting solution was stirred an additional 30 min at 0°C. then 16 h at RT. The reaction was quenched by the addition of brine,extracted with EtOAc (3×). The organic layers were combined, dried overanhydr. Na₂SO₄ filtered and the filtrate was concentrated in vacuo todryness. The residue was purified by silica gel chromatography usingEtOAc:petroleum ether to afford the title racemic compound I-21. Theracemic material was resolved using Chiral SFC (CHIRALPAK® OJ-H) toafford isomers I-21A (faster eluting) and I-21B (slower eluting). ¹H NMR(300 MHz, CDCl₃) δ 7.57 (d, J=8.7 Hz, 2H), 7.25 (d, J=7.8 Hz, 2H), 4.44(s, 1H), 4.33-4.20 (m, 2H), 1.98 (s, 3H), 1.25 (d, J=7.2 Hz, 3H);m/z=319 (M−1).

Intermediate 22 Methyl 1-(azidomethyl)cyclopropane-1-carboxylate

To a closed vial containing a solution of sodium azide (471 mg, 7.25mmol) in DMSO (40 mL) at RT was added methyl1-(bromomethyl)cyclopropanecarboxylate (1 g, 5.18 mmol). The resultingsolution was stirred 48 h at 45° C. The reaction was allowed to cooldown to RT and quenched by the addition of water. The mixture wasextracted with Et₂O (2×). The organic layer was dried over anhydr.MgSO₄, filtered and concentrated in vacuo to dryness to afford I-22.m/z=156 (M+1).

Intermediate 23 Methyl 2-azido-2-methylpropanoate

To a vial containing a solution of sodium azide (2.6 g, 40 mmol) andmethyl 2-bromo-2-methylpropanoate (1.3 mL, 10 mmol) in 10 mL of a 1:1DCM: water mixture at RT was added tetrabutylammonium hydrogen sulfate(700 mg, 2.0 mmol). The resulting solution was stirred 48 h at RT. Theorganic layer was washed with water (2×), dried over anhydr. MgSO₄,filtered and concentrated in vacuo to dryness to afford I-23. ¹H NMR(500 MHz, CDCl₃) δ 3.76 (s, 3H), 1.45 (s, 6H).

Intermediate 24B Ethyl3,3-dicyano-2-(1-(3-methoxy-3-oxopropyl)-1H-1,2,3-triazol-4-yl)-2-methylpropanoate

A flask under an inert atmosphere of nitrogen, was charged withethyl-2-(dicyanomethyl))-2-methylbut-3-ynoate I-10B (300 mg, 1.5 mmol),bromotris(triphenylphosphine)copper(I) (144 mg, 0.16 mmol) and DMSO (7.7mL). To this was added methyl 3-azidopropanoate (500 mg, 3.1 mmol) andthe reaction was stirred at 50° C. for 18 h. The reaction mixture wasdiluted with EtOAc, and water. The mixture was extracted with EtOAc(3×). The organic layer was washed with brine (2×), dried over anhydr.MgSO₄, and filtered. The filtrate was concentrated in vacuo. The residuewas purified by silica gel column chromatography with EtOAc:hexane(0-100%) to afford the title compound I-24B. ¹H NMR (500 MHz, CDCl₃) δ7.77 (s, 1H), 4.94 (s, 1H), 4.67 (t, J=6.3 Hz, 2H), 4.30 (qd, J=7.2, 1.3Hz, 2H), 3.70 (s, 3H), 2.99 (t, J=6.3 Hz, 2H), 1.95 (s, 3H), 1.30 (t,J=7.1 Hz, 3H); m/z=320 (M+1).

Using a similar procedure to that described for the synthesis ofintermediate I-24B, the following compounds in Table 2 were preparedfrom either commercial starting reagents or compounds known in theliterature.

TABLE 2

Int. R³ m/z (M + 1) 25B

306 26B

334 27B

348 28B

346

Intermediate 30 Diethyl 2-(dicyanomethyl)-2-methylmalonate

Using the procedure described in WO2015/088885 intermediate 30 wasprepared. ¹H NMR (500 MHz, CDCl₃): δ 4.55 (1H, s), 4.28-4.39 (4H, m),1.82 (3H, s), 1.34 (6H, t, J=7.12 Hz).

Intermediate 31 Diethyl cyclopropyl (dicyanomethyl)propanedioate

Using the procedure described in WO2015/088885 intermediate 31 wasprepared ¹H NMR (500 MHz, CDCl₃): δ 4.41 (s, 1H); 4.38-4.26 (m, 4H);1.52-1.45 (m, 1H); 1.33 (t, J=7.14 Hz, 6H); 0.86-0.79 (m, 2H); 0.71-0.66(m, 2H).

Intermediate 32 Ethyl3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)oxazol-2-yl)-2-methylpropanoate

Step A—Ethyl 3-amino-2-methyl-3-oxopropanoate

To a flask containing ethyl 2-cyanopropanoate (20 g, 157 mmol) at 0° C.was added dropwise chlorotrimethylsilane (40.2 mL, 315 mmol) followed bythe dropwise addition of water (5.7 mL, 315 mmol) maintaining thereaction temperature at 0° C. The reaction mixture was allow to warm upto RT and stirred for 4 h. The reaction mixture divided into two layers,and the supernatant was discarded. To this was added hexane and thesupernatant was discarded again. The residue was then neutralised by theaddition of a sat. aq. NaHCO₃ at 0° C. The mixture was extracted withEtOAc (3×). The organic layer was washed with brine (2×), dried overanhydr. MgSO₄, and filtered. The filtrate was concentrated in vacuo todryness to afford the title compound.

Step B—Methyl3-(2-(1-ethoxy-1-oxopropan-2-yl)oxazol-4-yl)-2,2-dimethylpropanoate

To a flask containing methyl 5-bromo-2,2-dimethyl-4-oxopentanoate (8.0g, 33.7 mmol), ethyl 3-amino-2-methyl-3-oxopropanoate (5.0 g, 34.4 mmol)in EtOAc (20 mL) was added silver trifluoromethanesulfonate (8.7 g, 33.7mmol). The resulting mixture stirred in the dark for 2 h at 90° C.,cooled to RT and filtered. The filtrate was concentrated in vacuo andthe residue was applied onto a C18 column with acetonitrile/water+0.1%TFA. The residue was purified by silica gel column chromatography withEtOAc:hexane to afford the title compound.

Step C—methyl3-(2-(2-bromo-1-ethoxy-1-oxopropan-2-yl)oxazol-4-yl)-2,2-dimethylpropanoate

To a flask containing methyl3-(2-(1-ethoxy-1-oxopropan-2-yl)oxazol-4-yl)-2,2-dimethylpropanoate (9.0g, 31.8 mmol) in THF (300 mL) at 0° C. was added dropwise a solution oflithium bis(trimethylsilyl)amide (34.9 mL, 34.9 mmol, 1 M in THF). Theresulting mixture was stirred for 30 min at 0° C. beforeN-bromosuccinimide (6.2 g, 34.9 mmol) was added in one portion. Theresulting mixture was stirred for 30 min at 0° C. then quenched by theaddition of sat. aq. NH₄Cl. The mixture was extracted with EtOAc (3×).The organic layer was washed with brine, dried over anhydr. Na₂SO₄,filtered and concentrated in vacuo. to dryness. The residue was purifiedby silica gel chromatography using an EtOAc/hexane gradient to affordthe title product.

Step D—Ethyl3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)oxazol-2-yl)-2-methylpropanoate

In a flask containing methyl3-(2-(2-bromo-1-ethoxy-1-oxopropan-2-yl)oxazol-4-yl)-2,2-dimethylpropanoate(6.16 g, 17.01 mmol), malononitrile (2.25 g, 34.0 mmol) in THF (200 mL)at 0° C. was added DBU (5.13 mL, 34.0 mmol). The resulting mixture wasstirred for 30 min at 0° C. then quenched by the addition of sat. aq.NH₄Cl. The mixture was extracted with EtOAc (3×). The organic layer waswashed with brine, dried over anhydr. Na₂SO₄, filtered and concentratedin vacuo to dryness. The residue was purified by silica gelchromatography using an EtOAc/hexane gradient to afford the racemicI-32. ¹H NMR (400 MHz, CDCl₃) δ 7.46 (s, 1H), 4.83 (s, 1H), 4.31 (q,J=7.2 Hz, 2H), 3.70 (s, 3H), 2.80 (s, 2H), 2.02 (s, 3H), 1.29 (t, J=7.2Hz, 3H), 1.23 (d, J=2.8 Hz, 6H); m/z=348 (M+1).

Using a similar procedure to that described for the synthesis ofintermediate 32, the following compounds in Table 3 were prepared fromcommercial starting reagents or compounds known in the literature. Theracemic material were resolved using chiral SFC (column, see table) toafford isomers A (faster eluting) and B (slower eluting).

TABLE 3

Chiral Resolution m/z Int. Column R³ (M + 1) 33A 33B AD

334 34A 34B AD

320

Intermediate 35, 35A and 35B Ethyl3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazol-2-yl)-2-methylpropanoateand the S and R Isomers Thereof

Step A—methyl3-(2-(1-ethoxy-1-oxopropan-2-yl)thiazol-4-yl)-2,2-dimethylpropanoate

A flask containing ethyl 3-amino-2-methyl-3-thioxopropanoate (6.1 g,37.8 mmol) and methyl 5-bromo-2,2-dimethyl-4-oxopentanoate (9.44 g, 37.8mmol) in EtOH (95 mL) was stirred at 50° C. for 1.5 h. The reaction wascooled to RT diluted with DCM and triethylamine (5.27 mL, 37.8 mmol) wasslowly added the resulting mixture was concentrated in vacuo to dryness.The residue was purified by silica gel column chromatography withEtOAc/Hexane gradient to afford the title compound. ¹H NMR (400 MHz,DMSO-d₆): δ 7.18 (s, 1H); 4.17 (q, J=8.0 Hz, 1H); 4.08 (q, J=8.0 Hz,2H); 3.05 (s, 3H); 2.88 (s, 2H), 1.45 (d, J=8.0 Hz, 3H), 1.13 (t, J=8.0Hz, 3H), 1.08 (s, 6H). m/z=300 (M+1).

Step B—methyl3-(2-(2-bromo-1-ethoxy-1-oxopropan-2-yl)thiazol-4-yl)-2,2-dimethylpropanoate

To a flask containing methyl3-(2-(1-ethoxy-1-oxopropan-2-yl)thiazol-4-yl)-2,2-dimethylpropanoate(10.5 g, 35.1 mmol) in toluene (175 mL) was added HCl (9.64 mL, 38.6mmol, 4M in dioxane) dropwise, and the resulting mixture was stirred 10min at RT. The reaction was cooled to 0° C. and KBr (4.59 g, 38.6 mmol)was added followed by the slow addition of H₂O₂ (3.99 mL, 45.6 mmol, 35wt %). The reaction was stirred at 0° C. for 30 min then quenched by theaddition of sodium thiosulfate (22.2 g, 140 mmol), diluted with waterand extracted with EtOAc (3×). The organic layers were combined, washedwith aq. sat. NaHCO₃, dried over anhydr. MgSO₄, and filtered. Thefiltrate was concentrated in vacuo to dryness to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆): δ 7.41 (s, 1H); 4.20 (q, J=8.0 Hz,2H); 3.56 (s, 3H); 2.90 (s, 2H), 2.24 (s, 3H), 1.18 (t, J=8.0 Hz, 3H),1.08 (s, 6H). m/z=378 (M+1).

Step C—ethyl3,3-dicyano-2-(4-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazol-2-yl)-2-methylpropanoate

To a flask containing methyl3-(2-(2-bromo-1-ethoxy-1-oxopropan-2-yl)thiazol-4-yl)-2,2-dimethylpropanoate(520 mg, 1.37 mmol) and malononitrile (182 mg, 2.75 mmol) in THF (14.5mL) at 0° C. was added dropwise 1,8-Diazabicycloundec-7-ene (0.41 mL,2.75 mmol). The resulting mixture was stirred for 30 min at 0° C. thenquenched by the addition of aq. sat. NH₄Cl and extracted with EtOAc(3×). The organic layers were combined, washed with brine, dried overanhydr. MgSO₄, and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography withEtOAc/Hexane gradient to afford the title racemic compound I-35. Theracemic material was resolved using chiral SFC (CHIRALPAK® IC column) toafford isomers I-35A (faster eluting) and I-35B (slower eluting). ¹H NMR(400 MHz, DMSO-d₆): δ 7.45 (s, 1H), 5.71 (s, 1H), 4.22 (q, J=8.0 Hz,2H), 3.58 (s, 3H), 2.94 (m, 2H), 1.86 (s, 3H), 1.17 (t, J=8.0 Hz, 3H),1.11 (s, 3H) 1.08 (s, 3H); m/z=364 (M+1).

Using a similar procedure to that described for the synthesis ofintermediate 35, the following compound in Table 4 was prepared. Theracemic material were resolved using chiral SFC (column, see table) toafford isomers A (faster eluting) and B (slower eluting).

TABLE 4

Chiral Reso- lution m/z Int. Column R³ (M + 1) 36A 36B AD-H

348 (M − 1)

Intermediate 37 37A and 37B Ethyl4-cyano-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-1H-pyrrole-3-carboxylate andthe S and R Isomers Thereof

To a flask containing a solution of I-18 (300 mg, 1.0 mmol) in 2.0 mLMeOH at RT was slowly added a solution of NaOMe (0.27 mL, 1.2 mmol, 25wt. % in MeOH). The resulting solution was stirred 6 h at 65° C. Thereaction was allowed to cool down to RT then quenched by the addition ofa aq. sol 1M KH₂PO₄ and EtOAc. The mixture was extracted with EtOAc(3×). The organic layer was washed with brine, dried over anhydr. MgSO₄,filtered and concentrated in vacuo. to dryness. The residue was purifiedby silica gel chromatography using an (EtOAc: EtOH 3:1):hexane gradientto afford the racemic title product I-37. The racemic material wasresolved using Chiral SFC (CHIRALPAK® AS-H) to afford isomers I-37A(faster eluting) and I-37B (slower eluting). ¹H NMR (400 MHz, CDCl₃) δ8.08 (t, J=1.8 Hz, 1H), 8.00 (dt, J=7.8, 1.4 Hz, 1H), 7.64 (ddd, J=7.9,2.1, 1.2 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.39 (s, 1H), 4.34 (s, 3H),3.93 (s, 3H), 1.84 (s, 3H); m/z 287 (M+1).

Intermediate 38, 38AA, 38AB, 38BA and 38BB Ethyl4-cyano-5-ethoxy-3-methyl-2-oxo-2,3-dihydro-1H-pyrrole-3-carboxylate andthe SS, SR, RS and RR Isomers Thereof

To a flask containing I-12 (683 mg, 2.0 mmol) in MeOH (4 mL) at RT wasadded sodium methoxide (0.55 mL, 2.4 mmol, 25 wt. % in MeOH), and themixture was stirred at 65° C. for 2 h. The reaction was allowed to cooldown to RT then quenched by the addition of a 1 M aq. solution of KH₂PO₄and EtOAc. The mixture was extracted with EtOAc (3×). The organic layerwas washed with brine, dried over anhydr. MgSO₄, filtered andconcentrated in vacuo to dryness. The residue was purified by silica gelchromatography using an (EtOAc: EtOH 3:1):hexane gradient to afford theracemic title product I-38. The racemic material was resolved usingchiral SFC (CHIRALPAK® AD-H column) to afford isomers I-38A (fastereluting) and I-38A (slower eluting). Isomer I-38A was resolved usingchiral SFC (CHIRALPAK® AD-H column) to afford isomers I-38AA (fastereluting) and I-38AB (slower eluting). Isomer I-38B was resolved usingchiral SFC (CHIRALPAK® AD-H column) to afford isomers I-38BA (fastereluting) and I-38BB (slower eluting).

Using a similar procedure to that described for the synthesis ofintermediate I-37 or I-38, the following compounds in Table 5 wereprepared

TABLE 5

Chiral Resolution Int. Column R³ R⁴ R⁵ m/z (M + 1) 39A 39B AS-H

Me Et 371 40A 40B AS-H

Me Et 239 41A 41B AS-H

Me 237 42A 42B IC

Me Me 334 43A 43B IC

Me Me 348 (M − 1)

Intermediate 44 Methyl 6-bromo-2,2-difluoro-5-oxohexanoate

To a flask containing ethyl 2,2-difluoro-5-oxohexanoate (12.0 g, 61.8mmol) in MeOH (30 mL) at 0° C. was added dropwise bromine (9.9 g, 61.8mmol). The resulting mixture was stirred for 16 h at RT. The reactionwas quenched by the addition of aq. sat. sodium thiosulfate andextracted with EtOAc (3×). The organic layers were combined, washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:petroleum ether to afford the title compoundI-44. ¹H NMR (300 MHz, CDCl₃) δ 3.88 (s, 2H), 3.23 (s, 3H), 2.99-2.83(m, 2H), 2.71-2.51 (m, 2H).

Intermediate 45 Methyl 6-bromo-2,2-dimethyl-5-oxohexanoate

Intermediate I-45 was prepared using a similar procedure to thatdescribed for the synthesis of intermediate I-44, using methyl2,2-dimethyl-5-oxohexanoate as starting material. ¹H NMR (300 MHz,CDCl₃) δ 3.88 (s, 2H), 3.67 (s, 3H), 2.67-2.61 (m, 2H), 1.81-1.83 (m,2H), 1.20 (s, 6H).

Intermediate 46 Methyl 5-bromo-2,2-dimethyl-4-oxohexanoate

Intermediate I-46 was prepared using a similar procedure to thatdescribed for the synthesis of intermediate I-7 usingmethyl-4-bromo-2,2-dimethylhex-4-enoate as starting material. ¹H NMR(300 MHz, CDCl₃) δ 4.40 (q, J=5.1 Hz, 1H), 3.70 (s, 3H), 3.09 (d, J=13.2Hz, 2H), 2.94 (d, J=13.2 Hz, 2H), 1.74 (d, J=5.1 Hz, 3H), 1.24 (s, 6H).

Intermediate 47(R)-methyl-2-{[(9H-fluoren-9-yl)methoxy]carbonylamino}-5-bromo-4-oxopentanoate

StepA—(R)-methyl-2-{[(9H-fluoren-9-yl)methoxy]carbonylamino}-4-bromopent-4-enoate

To a flask containing(R)-2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4-bromopent-4-enoicacid (1.9 g, 4.56 mmol) in MeOH (30 mL) at 0° C. was added sulfuryldichloride (62 mg, 0.46 mmol) dropwise. The resulting mixture wasstirred at RT for 16 h then quenched by the addition of water. Themixture was extracted with EtOAc (3×). The organic layer was washed withaq. sat. NaHCO₃ and brine, dried over anhydr. Na₂SO₄, filtered andconcentrated in vacuo to afford the title product. m/z=430, 432 (M+1).

StepB—(R)-methyl-2-{[(9H-fluoren-9-yl)methoxy]carbonylamino}-5-bromo-4-oxopentanoate

To a flask containing (R)-methyl2-({[(9H-fluoren-9-yl)methoxy]carbonyl}amino)-4-bromopent-4-enoate (300mg, 0.70 mmol) in a DMF (3 mL)-water (15 mL) mixture at 0° C. was addedin portions N-bromosuccinimide (136 mg, 0.77 mmol). The resultingmixture was stirred at RT for 16 h then diluted with EtOAc (100 mL),washed with brine, dried over anhydr. Na₂SO₄, filtered and concentratedin vacuo to dryness. The residue was purified by silica gelchromatography using an EtOAc:petroleum ether gradient to afford thetitle product I-47 m/z=446, 448 (M+1).

Intermediates 48-52

Using a similar procedure described for the synthesis of intermediatesI-10 or I-11, the following compounds in Table 6 were prepared fromcommercial starting reagents or compounds known in the literature.Racemic material was resolved using chiral SFC or HPLC (column, seetable) to afford isomers A (faster eluting) and B (slower eluting).

TABLE 6

Chiral Resolution m/z Int. Column R³ (M + 1) 48A 48B AD-H

301 49 —

343 (M − 1) 50A 50B OJ-H

271 (M − 1) 51A 51B IF

344 52 —

322

Intermediates 53-57

Using a similar procedure to that described for the synthesis ofintermediate I-32, the following compounds in Table 7 were prepared fromcommercial starting reagents or compounds known in the literature.Racemic material was resolved using chiral SFC or HPLC (column, seetable) to afford isomers A (faster eluting) and B (slower eluting).

TABLE 7

Chiral Resolution Int. Column R³ m/z (M + 1) 53A 53B AS

382 54 —

384 55A 55B AS-H

362 56A 56B OJ-H

362 57A 57B AD-H

557

Intermediates 58-59

Using a similar procedure to that described for the synthesis ofintermediate I-35, the following compounds in Table 8 was prepared.Racemic material was resolved using chiral SFC or HPLC (column, seetable) to afford isomers A (faster eluting) and B (slower eluting).

TABLE 8

Chiral Resolution Int. Column R³ m/z (M + 1) 58A 58B IF

396 (M − 1) 59A 59B AD-H

376 (M − 1)

Intermediates 60-61

Using a similar procedure to that described for the synthesis ofintermediate I-24, the following compounds in Table 9 were prepared fromeither commercial starting reagents or compounds known in theliterature.

TABLE 9

Int. R³ m/z (M + 1) 60

362 61

348

Intermediate 62 Ethyl3,3-dicyano-2-(5-(3-ethoxy-3-oxopropyl)pyridin-2-yl)-2-methylpropanoate

To a flask under an inert atmosphere of nitrogen, containing I-19 (450mg, 1.40 mmol) and 2nd generation XPhos precatalyst(chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II), 220 mg, 0.28 mmol) in THF (16mL) was added (3-ethoxy-3-oxopropyl)zinc(II) bromide (16.8 mL, 8.38mmol, 0.5 M in THF). The resulting mixture was stirred for 6 h at 50° C.then quenched by the addition of aq. sat. NH₄Cl and extracted with EtOAc(3×). The organic layers were combined, washed with brine, dried overanhydr. MgSO₄, and filtered. The filtrate was concentrated in vacuo. Theresidue was then purified by reverse phase HPLC (ACN/water with 0.05%NH₄HCO₃ modifier) to afford the title compound I-62. ¹H NMR (300 MHz,CDCl₃) δ 8.41 (d, J=2.4 Hz, 1H), 7.61 (dd, J=8.1, 2.4 Hz, 1H), 7.39 (dd,J=8.1, 0.9 Hz, 1H), 5.20 (s, 1H), 4.25-4.05 (m, 4H), 2.95 (t, J=7.5 Hz,2H), 2.61 (t, J=7.5 Hz, 2H), 1.95 (s, 3H), 1.23-1.17 (m, 6H); m/z=342(M−1).

Intermediate 63, 63A and 63B Ethyl3,3-dicyano-2-[1-(3-methoxy-2,2-dimethyl-3-oxopropyl)-1H-pyrazol-4-yl]-2-methylpropanoateand the S and R Isomers Thereof

Step A—Methyl 2,2-dimethyl-3-(1H-pyrazol-1-yl)propanoate

A mixture containing 1H-pyrazole (5.2 g, 77 mmol), methyl2,2-dimethyl-3-(tosyloxy)propanoate (20 g, 69.8 mmol) and cesiumcarbonate (29.6 g, 91 mmol) in DMF (70 mL) was stirred in a flask at 80°C. for 48 h. The reaction was then quenched by the addition of water andextracted with EtOAc (3×). The organic layers were combined, washed withbrine, dried over anhydr. NaSO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was then purified by reverse phaseHPLC (ACN/water with 0.1% TFA modifier) to afford the title compoundm/z=183 (M+1).

Step B—Methyl3-[4-(2-ethoxy-2-oxoacetyl)-1H-pyrazol-1-yl]-2,2-dimethylpropanoate

A mixture containing methyl 2,2-dimethyl-3-(1H-pyrazol-1-yl)propanoate(3.6 g, 19.76 mmol) and ethyl 2-chloro-2-oxoacetate (10 mL, 89 mmol) wasstirred in a flask for 24 h at 100° C. The reaction mixture was thenquenched by the addition of iced water. The pH was adjusted to pH 8 bythe addition of NaHCO₃. The resulting mixture was extracted with EtOAc(3×). The organic layers were combined, washed with brine, dried overanhydr. NaSO₄, and filtered. The filtrate was concentrated in vacuo. Theresidue was then purified by reverse phase HPLC (ACN/water with 0.1% TFAmodifier) to afford the title compound m/z=283 (M+1).

Step C—Ethyl3,3-dicyano-2-[1-(3-methoxy-2,2-dimethyl-3-oxopropyl)-1H-pyrazol-4-yl]acrylate

A flask containing methyl3-[4-(2-ethoxy-2-oxoacetyl)-1H-pyrazol-1-yl]-2,2-dimethylpropanoate (1.4g, 4.96 mmol), malononitrile (1.31 g, 19.84 mmol) and piperidine (84 mg,0.99 mmol) in EtOH (10 mL) was stirred at RT for 16 h. The mixture wasconcentrated in vacuo and the residue was then purified by reverse phaseHPLC (ACN/water with 0.1% TFA modifier) to afford the title compoundm/z=331 (M+1).

Step D—Ethyl3,3-dicyano-2-[1-(3-methoxy-2,2-dimethyl-3-oxopropyl)-1H-pyrazol-4-yl]-2-methylpropanoate

To a flask under an inert atmosphere of nitrogen, containing ethyl3,3-dicyano-2-[1-(3-methoxy-2,2-dimethyl-3-oxopropyl)-1H-pyrazol-4-yl]acrylate(1.4 g, 4.24 mmol) and lithium chloride (0.36 g, 8.48 mmol) in THF (40mL) at 0° C. was added methylmagnesium bromide (8.5 mL, 8.5 mmol, 1M inTHF) dropwise. The resulting mixture was stirred for 1 h at 0° C., thenthe reaction was quenched by the addition of aq. sat. NH₄Cl, extractedwith EtOAc (3×). The organic layers were combined, washed with brine,dried over anhydr. NaSO₄, and filtered. The filtrate was concentrated invacuo. The residue was then purified by reverse phase HPLC (ACN/waterwith 0.1% TFA modifier) to afford the title racemic product I-63. Theracemic material was resolved using chiral SFC (CHIRALPAK® AD-H) toafford isomers I-63A (faster eluting) and I-63B (slower eluting). ¹H NMR(400 MHz, CDCl₃) δ 7.50 (d, J=0.8 Hz, 1H), 7.48 (d, J=0.9 Hz, 1H), 4.41(s, 1H), 4.34-4.28 (m, 4H), 3.73 (s, 3H), 1.91 (s, 3H), 1.32 (t, J=7.2Hz, 3H), 1.22 (s, 3H), 1.21 (s, 3H); m/z=347 (M+1).

Intermediate 64 Ethyl3,3-dicyano-2-[2-(3-methoxy-2,2-dimethyl-3-oxopropyl)oxazol-4-yl]-2-methylpropanoate

Step A—Methyl 4-amino-2,2-dimethyl-4-oxobutanoate

To a flask containing 4-methoxy-3,3-dimethyl-4-oxobutanoic acid (5 g,31.2 mmol) in DCM (50 mL) at 0° C. was added oxalyl chloride (15 mL, 171mmol) and a drop of DMF. The resulting mixture was stirred for 3 h atRT. The reaction mixture was concentrated in vacuo. The residue wasdissolved in THF (20 mL), and added to a solution of ammonia hydrate(28%, 20 mL) in THF (20 mL) at 0° C. The resulting mixture was stirredfor 15 min at 0° C. then concentrated in vacuo. The residue wasdissolved in EtOAc, dried over anhydr. Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo to afford the title compound.

Step B—Methyl3-[4-(1-ethoxy-1-oxopropan-2-yl)oxazol-2-yl]-2,2-dimethylpropanoate

A flask containing methyl 4-amino-2,2-dimethyl-4-oxobutanoate (4 g, 25.1mmol), ethyl 4-bromo-2-methyl-3-oxobutanoate (6.7 g, 30.2 mmol) andsilver trifluoromethanesulfonate (6.78 g, 26.4 mmol) in EtOAc (50 mL)was stirred at 90° C. for 4 h. The reaction mixture was cooled andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) toafford the title compound.

Step C—Methyl3-[4-(2-bromo-1-ethoxy-1-oxopropan-2-yl)oxazol-2-yl]-2,2-dimethylpropanoate

To a flask, under an inert atmosphere of nitrogen, containing methyl3-[4-(1-ethoxy-1-oxopropan-2-yl)oxazol-2-yl]-2,2-dimethylpropanoate (1.2g, 4.24 mmol) in THF (10 mL) at 0° C. was added dropwise lithiumbis(trimethylsilyl)amide (5.08 mL, 5.08 mmol). The resulting mixture wasstirred for 30 min at 0° C. then a solution of N-bromosuccinimide (0.98g, 5.51 mmol) in THF (5 mL) was added and the mixture was stirred for 30min at 0° C. The reaction was quenched by the addition of aq. sat.NH₄Cl, and extracted with EtOAc (3×). The organic layer was washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:petroleum ether to afford the title compound.

Step D—Ethyl3,3-dicyano-2-[2-(3-methoxy-2,2-dimethyl-3-oxopropyl)oxazol-4-yl]-2-methylpropanoate

To a flask, under an inert atmosphere of nitrogen, containing methyl3-[4-(2-bromo-1-ethoxy-1-oxopropan-2-yl)oxazol-2-yl]-2,2-dimethylpropanoate(750 mg, 2.07 mmol) and malononitrile (684 mg, 10.35 mmol) in DMSO (100mL) at 15° C. was added potassium carbonate (715 mg, 5.18 mmol) inportions. The resulting mixture was stirred for 1 h at RT. The reactionwas quenched by the addition of aq. sat. NH₄Cl, extracted with EtOAc(3×). The organic layer was washed with brine, dried over anhydr.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography withEtOAc:petroleum ether to afford the title compound I-64. ¹H NMR (300MHz, CDCl₃) δ 7.60 (s, 1H), 4.79 (s, 1H), 4.25 (q, J=7.2 Hz, 2H), 3.66(s, 3H), 2.99 (s, 2H), 1.83 (s, 3H), 1.28-1.22 (m, 9H); m/z=348 (M+1).

Intermediate 65, 65A and 65B Ethyl3,3-dicyano-2-[2-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazol-4-yl]-2-methylpropanoateand the S and R Isomers Thereof

Step A—Methyl 4-amino-2,2-dimethyl-4-thioxobutanoate

To a flask containing methyl 4-amino-2,2-dimethyl-4-oxobutanoate (5.1 g,32.0 mmol) in THF (200 mL) at 0° C. was added phosphorus pentasulfide(21.4 g, 96 mmol). The resulting mixture was stirred for 16 h at RT. Thereaction mixture was filtered and the filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography withEtOAc:petroleum ether to afford the title compound.

Step B—Methyl3-[4-(1-ethoxy-1-oxopropan-2-yl)thiazol-2-yl]-2,2-dimethylpropanoate

A flask containing methyl 4-amino-2,2-dimethyl-4-thioxobutanoate (1.65g, 9.42 mmol) and ethyl 4-bromo-2-methyl-3-oxobutanoate (3.50 g, 9.42mmol) in EtOH (20 mL) was stirred at 50° C. for 30 min. The reactionmixture was concentrated in vacuo. The residue was purified by silicagel column chromatography with MeOH:DCM (0-5%). The residue was dilutedwith EtOAc and washed with aq. sat. NaHCO₃, dried over anhydr. Na₂SO₄,and filtered. The filtrate was concentrated in vacuo to afford the titlecompound. m/z=300 (M+1).

Step C—Methyl3-[4-(2-bromo-1-ethoxy-1-oxopropan-2-yl)thiazol-2-yl]-2,2-dimethylpropanoate

To a flask under an inert atmosphere of nitrogen, containing methyl3-[4-(1-ethoxy-1-oxopropan-2-yl)thiazol-2-yl]-2,2-dimethylpropanoate(1.87 g, 6.25 mmol) in THF (40 mL) at 0° C. was added dropwise lithiumbis(trimethylsilyl)amide (6.87 mL, 6.87 mmol, 1M in THF). The resultingmixture was stirred at 0° C. for 30 min then a solution ofN-bromosuccinimide (1.223 g, 6.87 mmol) in THF (4 mL) was added. Theresulting mixture was stirred at 0° C. for another 30 min, then quenchedby the addition of aq. sat. NH₄Cl, and extracted with EtOAc (3×). Theorganic layer was washed with brine, dried over anhydr. Na₂SO₄, filteredand the filtrate was concentrated in vacuo. The residue was purified byreverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford thetitle compound. m/z=378, 380 (M+1).

Step D—Ethyl3,3-dicyano-2-[2-(3-methoxy-2,2-dimethyl-3-oxopropyl)thiazol-4-yl]-2-methylpropanoate

To a flask, containing methyl3-[4-(2-bromo-1-ethoxy-1-oxopropan-2-yl)thiazol-2-yl]-2,2-dimethylpropanoate(560 mg, 1.48 mmol) and malononitrile (489 mg, 7.40 mmol) in DMSO (20mL) at 15° C. was added potassium carbonate (511 mg, 3.70 mmol). Theresulting mixture was stirred for 1 h at RT. The reaction was quenchedby the addition of aq. sat. NH₄Cl, and extracted with EtOAc (3×). Theorganic layer was washed with brine, dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by reverse phase HPLC (ACN/water with 0.1% TFA modifier) toafford the racemic title compound I-65. The racemic material wasresolved using Chiral HPLC (CHIRALPAK® IF) to afford isomer I-65A(faster eluting) and isomer I-65B (slower eluting). ¹H NMR (400 MHz,CDCl₃) δ 7.27 (s, 1H), 5.05 (s, 1H), 4.26 (q, J=7.2 Hz, 2H), 3.73 (s,3H), 3.24 (s, 2H), 1.97 (s, 3H), 1.29-1.25 (m, 9H); m/z=364 (M+1).

Intermediate 66, 66A and 66B Methyl2-(1,1-dicyano-3-ethoxy-2-methyl-3-oxopropan-2-yl)benzo[d]oxazole-5-carboxylateand the S and R Isomers Thereof

Step A—2-(1-Ethoxy-1-oxopropan-2-yl)benzo[d]oxazole-5-carboxylate

A flask containing methyl 3-amino-4-hydroxybenzoate (5.0 g, 29.9 mmol),and diethyl 2-methylmalonate (15.6 g, 90 mmol) was stirred at 160° C.for 8 h. To this was added 4-methylbenzenesulfonic acid (1.0 g, 5.98mmol). The resulting mixture was stirred for an additional 10 h at 160°C. then filtered. The filtrate was applied onto silica gel columnchromatography with EtOAc:petroleum ether to afford the title compoundm/z=278 (M+1).

Step B—Methyl2-(2-bromo-1-ethoxy-1-oxopropan-2-yl)benzo[d]oxazole-5-carboxylate

To a flask, containing methyl2-(1-ethoxy-1-oxopropan-2-yl)benzo[d]oxazole-5-carboxylate (3 g, 10.82mmol) in THF (100 mL) at 0° C. was added lithiumbis(trimethylsilyl)amide (14.1 mL, 14.10 mmol, 1M in THF). The resultingmixture was stirred for 15 min at 0° C. then a solution ofN-bromosuccinimide (2.89 g, 16.23 mmol) in THF (10 mL) was added. Theresulting mixture was stirred for 30 min at 0° C. then quenched by theaddition of aq. sat. NH₄Cl and extracted with EtOAc (3×). The organiclayers were combined, washed with brine, dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography with EtOAc:petroleum etherto afford the title compound. m/z=356, 358 (M+1).

Step C—Methyl2-(1,1-dicyano-3-ethoxy-2-methyl-3-oxopropan-2-yl)benzo[d]oxazole-5-carboxylate

To a flask containing methyl2-(2-bromo-1-ethoxy-1-oxopropan-2-yl)benzo[d]oxazole-5-carboxylate (1.5g, 4.21 mmol) and malononitrile (1.39 g, 21.06 mmol) in DMSO (40 mL) at15° C. was added potassium carbonate (1.46 g, 10.53 mmol) portionwise.The resulting mixture was stirred for 1 h at RT, then quenched by theaddition of aq. sat. NH₄Cl and extracted with EtOAc (3×). The organiclayers were combined, washed with brine, dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) toafford racemic I-66. The racemic material was resolved using Chiral HPLC(CHIRALPAK® ID) to afford isomer I-66A (faster eluting) and isomer I-66B(slower eluting)¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 8.20 (d, J=8.8Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 4.98 (s, 1H), 4.35 (q, J=7.2 Hz, 2H),3.99 (s, 3H), 2.17 (s, 3H), 1.31 (t, J=7.2 Hz, 3H); m/z=342 (M+1).

Intermediate 67 Methyl2-(1,1-dicyano-3-ethoxy-2-methyl-3-oxopropan-2-yl)benzo[d]thiazole-5-carboxylate

Step A—Methyl2-(1-ethoxy-1-oxopropan-2-yl)benzo[d]thiazole-5-carboxylate

A flask under an inert atmosphere of nitrogen, containing methyl3-amino-4-mercaptobenzoate hydrochloride (8.4 g, 38.20 mmol) and ethyl2-cyanopropanoate (4.9 g, 38.20 mmol) was stirred for 2 h at 120° C. Thereaction was quenched by the addition of water and extracted with EtOAc(3×). The organic layers were combined, washed with brine, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography withEtOAc:petroleum ether (0-50%). The residue was purified by reverse phaseHPLC (ACN/water with 0.1% TFA modifier) to afford the title compound.m/z=294 (M+1).

Step B—Methyl2-(2-bromo-1-ethoxy-1-oxopropan-2-yl)benzo[d]thiazole-5-carboxylate

To a flask under an inert atmosphere of nitrogen, containing methyl2-(1-ethoxy-1-oxopropan-2-yl)benzo[d]thiazole-5-carboxylate (457 mg,1.56 mmol) in THF (20 mL) at 0° C. was added dropwise a solution oflithium bis(trimethylsilyl) amide (1.56 mmol, 1.56 mL, 1 M in THF). Themixture was stirred for 15 min at 0° C. before N-bromosuccinimide (305mg, 1.714 mmol) was added. The resulting mixture was stirred for 30 minat 0° C., then quenched by the addition of aq. sat. NH₄Cl and extractedwith EtOAc (3×). The organic layers were combined, washed with brine,dried over anhydr. Na₂SO₄, and filtered. The filtrate was concentratedin vacuo. The residue was purified by silica gel column chromatographywith EtOAc:petroleum ether (0-10%) to afford the title compound.m/z=372, 374 (M+1).

Step C. Methyl2-(1,1-dicyano-3-ethoxy-2-methyl-3-oxopropan-2-yl)benzo[d]thiazole-5-carboxylate

To a flask containing methyl2-(2-bromo-1-ethoxy-1-oxopropan-2-yl)benzo[d]thiazole-5-carboxylate (269mg, 0.72 mmol) and malononitrile (286 mg, 4.34 mmol) in DMSO (5 mL) at15° C. was added potassium carbonate (300 mg, 2.17 mmol). The resultingmixture was stirred for 1 h at RT, then the reaction mixture wasquenched by the addition of aq. sat. NH₄Cl and extracted with EtOAc(3×). The organic layers were combined, washed with brine, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo.The residue was purified by reverse phase HPLC (ACN/water with 0.1% TFAmodifier) to afford the title compound. ¹H NMR (400 MHz, CDCl₃) δ 8.76(d, J=1.6 Hz 1H), 8.17 (dd, J=1.6, 8.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H),5.27 (s, 1H), 4.38 (q, J=7.2 Hz, 2H), 3.99 (s, 3H), 2.17 (s, 3H), 1.34(t, J=7.2 Hz, 3H); m/z=358 (M+1).

Intermediate 68 Methyl2-(4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-3,3-dicyano-2-methylpropanoate

Step A—(4-Bromocyclohexyl)methanol

To a flask containing LiAlH₄ (5.6 g, 148 mmol) in THF (200 mL) at 0° C.was added dropwise a solution of ethyl 4-bromocyclohexane carboxylate(31.2 g, 133 mmol) in THF (50 mL). The resulting mixture was stirred at0° C. for 1 h. The reaction mixture was slowly quenched by the additionof water (5.6 mL) at 0° C. Then to this, was added sodium hydroxide(15%, 5.6 mL) and water (16.8 mL). The resulting mixture was stirred for15 min. To this was added anhydr. MgSO₄. The resulting mixture wasstirred for 15 min, and filtered. The filtrate was concentrated in vacuoto give the title compound.

Step B—[(4-Bromocyclohexyl)methoxyl](tert-butyl)dimethylsilane

To a flask containing (4-bromocyclohexyl)methanol (25.1 g, 130 mmol) andtert-butylchlorodimethylsilane (21.6 g, 143 mmol) in DMF (100 mL) at 0°C. was added portionwise imidazole (11.5 g, 169 mmol). The resultingmixture was stirred for 3 h at RT. The reaction was then quenched by theaddition of water and extracted with EtOAc (3×). The organic layers werecombined, washed with brine, dried over anhydr. NaSO₄, and filtered. Thefiltrate was concentrated in vacuo. The residue was purified by silicagel chromatography using an EtOAc:petroleum ether gradient to afford thetitle compound.

Step C—Methyl2-(4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-2-oxoacetate

To a flask under an inert atmosphere of nitrogen, containing magnesiumturnings (0.79 g, 32.5 mmol), a few drops of[(4-bromocyclohexyl)methoxy](tert-butyl)dimethylsilane and iodine (0.21g, 0.81 mmol) in diethyl ether (5 mL) was heated to reflux. A solutionof [(4-bromocyclohexyl)methoxy](tert-butyl)dimethylsilane (5 g, 16.27mmol) in diethyl ether (40 mL) was added dropwise to the reaction overapproximately 1.5 h, maintaining the reaction mixture at reflux. Thereaction was stirred at reflux for an additional 1 h then cooled to RT.This reaction mixture was added dropwise to a flask under an inertatmosphere of nitrogen, containing dimethyl oxalate (2.50 g, 21.15 mmol)in a diethyl ether (30 mL)−THF (50 mL) mixture at 0° C. The resultingmixture was stirred for 2 h at RT. The reaction was then quenched by theaddition of aq. sat. NH₄Cl and extracted with diethyl ether (3×). Theorganic layers were combined, washed with brine, dried over anhydr.NaSO₄, and filtered. The filtrate was concentrated in vacuo. The residuewas purified by silica gel chromatography using an EtOAc:petroleum ethergradient to afford the title compound ¹H NMR (400 MHz, CDCl₃) δ3.92-3.88 (m, 3H), 3.48-3.41 (m, 2H), 2.10-1.80 (m, 4H), 1.70-1.25 (m,4H), 1.10-0.95 (m, 1H), 0.95-0.90 (m, 10H), 0.07-0.05 (m, 6H).

Step D—Methyl2-(4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-3,3-dicyanoacrylate

Into a flask were placed methyl2-(4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-2-oxoacetate (2.7g, 8.59 mmol), malononitrile (1.13 g, 17.17 mmol), 3-aminopropanoic acid(0.23 g, 2.58 mmol), and water (20 mL). The resulting mixture wasstirred for 15 min at RT before ethanol (20 mL) was added, and themixture was stirred at RT for an additional 2 h. The reaction was thenquenched by the addition of brine and extracted with EtOAc (3×). Theorganic layers were combined, washed with brine, dried over anhydr.NaSO₄, and filtered. The filtrate was concentrated in vacuo. The residuewas purified by silica gel chromatography using an EtOAc:petroleum ethergradient to afford the title compound.

Step E—Methyl2-(4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-3,3-dicyano-2-methylpropanoate

To a flask, under an inert atmosphere of nitrogen, containing methyl2-(4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-3,3-dicyanoacrylate(2.2 g, 6.07 mmol) and lithium chloride (0.77 g, 18.20 mmol) in THF (30mL) at 0° C. was added methylmagnesium bromide (4.1 mL, 12.14 mmol, 3Min diethyl ether) dropwise. The resulting mixture was stirred for 1 h at0° C., then quenched by the addition of aq. sat. NH₄Cl and extractedwith EtOAc (3×). The organic layers were combined, washed with brine,dried over anhydr. NaSO₄, and filtered. The filtrate was concentrated invacuo. The residue was purified by silica gel chromatography using anEtOAc:petroleum ether gradient to afford the title compound I-68. ¹H NMR(400 MHz, CDCl₃) δ 4.34-4.30 (m, 1H), 3.83-3.82 (brs, 3H), 3.41 (d,J=6.4 Hz, 2H), 1.90-1.65 (m, 5H), 1.57 (s, 3H), 1.40-1.35 (m, 1H),1.15-0.80 (m, 13H), 0.06-0.04 (m, 6H); m/z=377 (M−1).

Intermediate 69, 69A and 69B Ethyl3,3-dicyano-2-(3-cyanophenyl)-2-methylpropanoate and the S and R IsomersThereof

Step A—Ethyl 2-bromo-2-(3-bromophenyl)propanoate

A flask, under an inert atmosphere of nitrogen, containing ethyl2-(3-bromophenyl)propanoate (21 g, 73.5 mmol), N-bromosuccinimide (15.7g, 88 mmol) and azodiisobutyronitrile (1.2 g, 7.35 mmol) intetrachloromethane (300 mL) was stirred at 80° C. for 1.5 h. Thereaction mixture was cooled to RT, quenched by the addition of aq. sat.sodium bisulfate, and extracted with EtOAc (3×). The organic layers werecombined, washed with brine, dried over anhydr. Na₂SO₄, and filtered.The filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography with EtOAc:petroleum ether (0-30%) toafford the title compound.

Step B—Ethyl 2-(3-bromophenyl)-3,3-dicyano-2-methylpropanoate

To a flask, under an inert atmosphere of nitrogen, containingmalononitrile (1.24 g, 18.8 mmol) in DMF (30 mL) at 0° C. was added inportions sodium hydride (0.56 g, 14.1 mmol, 60%). The mixture wasstirred for 30 min at 0° C. before ethyl2-bromo-2-(3-bromophenyl)propanoate (3.5 g, 9.37 mmol) was added. Theresulting mixture was stirred for 1 h at 0° C., then quenched by theaddition of water and extracted with EtOAc (3×). The organic layers werecombined, washed with brine, dried over anhydr. Na₂SO₄, and filtered.The filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography with EtOAc:petroleum ether (0-50%) toafford the title compound. ¹H NMR (300 MHz, CDCl₃) δ 7.59-7.51 (m, 2H),7.36-7.29 (m, 2H), 4.47 (s, 1H), 4.34-4.23 (m, 2H), 1.98 (s, 3H), 1.26(t, J=7.2 Hz, 3H).

Step C—Ethyl 3,3-dicyano-2-(3-cyanophenyl)-2-methylpropanoate

A flask under an inert atmosphere of nitrogen, containing ethyl2-(3-bromophenyl)-3,3-dicyano-2-methylpropanoate (2.5 g, 7.39 mmol),1,1′-bis(diphenylphosphino)ferrocene (0.82 g, 1.479 mmol), zinc cyanide(1.13 g, 9.61 mmol), zinc (0.24 g, 3.70 mmol),tris(dibenzylideneacetone)dipalladium chloroform adduct (0.76 g, 0.739mmol) in DMA (25 mL) was stirred for 16 h at 120° C. The mixture wascooled to RT, quenched by the addition of water and extracted with EtOAc(3×). The organic layers were combined, washed with brine, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography withEtOAc:petroleum ether (0-50%) to afford the racemic title compound I-69.The racemic material was resolved using Chiral HPLC (Chiralcel OJ-H) toafford isomer I-69A (faster eluting) and isomer I-69B (slower eluting)¹HNMR (300 MHz, CDCl₃) δ 7.76-7.57 (m, 4H), 4.49 (s, 1H), 4.39-4.23 (m,2H), 2.02 (s, 3H), 1.27 (t, J=7.2 Hz, 3H); m/z=266 (M−1).

Intermediate 70A Ethyl 3,3-dicyano-2-(4-cyanophenyl)-2-methylpropanoate

A flask under an inert atmosphere of nitrogen, containing I-21A (320 mg,1.00 mmol), 1,1′-bis(diphenylphosphino)ferrocene (50 mg, 0.09 mmol),zinc powder (32 mg, 0.49 mmol), zinc cyanide (150 mg, 1.29 mmol) andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (60 mg, 0.06mmol) in DMA (10 mL) was stirred for 2 h at 120° C. The reaction wascooled to RT and quenched by the addition of water and extracted withEtOAc (3×). The organic layers were combined, washed with brine, driedover anhydr. Na₂SO₄, and filtered. The filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography withEtOAc:petroleum ether (0-20%) to afford the title compound I-70A. ¹H NMR(400 MHz, CDCl₃) δ 7.79 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 4.50(s, 1H), 4.39-4.26 (m, 2H), 2.04 (s, 3H), 1.29 (t, J=7.2 Hz, 3H); m/z266 (M−1).

Intermediate 71, 71A and 71B Methyl3,3-dicyano-2-(5-cyanopyridin-2-yl)-2-methylpropanoate and the S and RIsomers Thereof

Step A—Ethyl 2 (5-bromopyridin-2-yl)propanoate

To a flask, containing ethyl 2-(5-bromopyridin-2-yl)acetate (4 g, 16.39mmol) in THF (20 mL) at 0° C. was added dropwise lithiumbis(trimethylsilyl)amide (18.2 mL, 18.7 mmol, 1 M in THF). The resultingsolution was stirred at 0° C. for 30 min, and iodomethane (2.3 g, 16.20mmol) was added. The resulting solution was stirred 2 h at RT thenquenched by the addition of water and extracted with EtOAc (3×). Theorganic layers were combined, washed with brine, dried over anhydr.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography withEtOAc:petroleum ether (0-10%) to afford the title compound.

Step B—Ethyl 2-(5-cyanopyridin-2-yl)propanoate

A flask, under an inert atmosphere of nitrogen, containing ethyl2-(5-bromopyridin-2-yl)propanoate (3.8 g, 14.72 mmol), dicyanozinc (2.25g, 19.14 mmol), zinc (0.48 g, 7.36 mmol), tris(dienzylideneacetone)dipalladium-chloroform adduct (1.52 g, 1.472 mmol) and 1,1′-ferrocenebis(diphenylphosphine) (1.63 g, 2.94 mmol) in DMA (30 mL) was stirred at120° C. for 2 h. The mixture was cooled, diluted with a mixture DCM/MeOH(1/1) (100 mL). The solid was filtered out, and the filtrate wasconcentrated in vacuo. Water was added to the residue and the mixturewas extracted with EtOAc (3×). The organic layers were combined, washedwith brine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with MeOH:DCM (0-10%) to afford the title compound.

Step C—Ethyl 2-bromo-2-(5-cyanopyridin-2-yl)propanoate

A flask, under an inert atmosphere of nitrogen, containing ethyl2-(5-cyanopyridin-2-yl)propanoate (2.5 g, 12.24 mmol),N-bromosuccinimide (2.83 g, 15.91 mmol) and 2,2′-azobisisobutyronitrile(0.20 g, 1.22 mmol) in carbontetrachloride (25 mL) was stirred for 4 hat 80° C. The reaction was cooled, quenched by the addition of water andextracted with DCM (3×). The organic layers were combined, washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:petroleum ether (0-10%) to afford the titlecompound.

Step D—Ethyl 3,3-dicyano-2-(5-cyanopyridin-2-yl)-2-methylpropanoate

To a flask containing sodium hydride (0.28 g, 7.06 mmol) in DMF (12 mL)at 0° C., was added dropwise a solution of malononitrile (0.47 g, 7.06mmol) in DMF (2 mL). The mixture was stirred for 15 min at 0° C., thenethyl 2-bromo-2-(5-cyanopyridin-2-yl)propanoate (1.0 g, 3.53 mmol) wasadded. The reaction mixture was stirred for 2 h at 0° C. The reactionwas quenched by the addition of water and extracted with EtOAc (3×). Theorganic layers were combined, washed with brine, dried over anhydr.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography withEtOAc:petroleum ether (0-10%) to afford theracemic title compound I-71.The racemic material was resolved using Chiral HPLC (CHIRALPAK® AS-H) toafford isomer I-71A (faster eluting) and isomer I-71B (slower eluting).¹H NMR (300 MHz, CDCl₃) δ 8.85 (dd, J=2.1, 0.9 Hz, 1H), 8.07 (dd, J=8.4,2.1 Hz, 1H), 7.65 (dd, J=8.4, 0.9 Hz, 1H), 5.11 (s, 1H), 4.29-4.18 (m,2H), 2.00 (s, 3H), 1.23 (t, J=7.2 Hz, 3H); m/z=269 (M+1).

Intermediate 72 Ethyl3,3-dicyano-2-(6-cyanopyridin-2-yl)-2-methylpropanoate

A flask purged and maintained with an inert atmosphere of nitrogen,containing I-52 (197 mg, 1.68 mmol),tris(dibenzylideneacetone)dipalladium chloroform adduct (145 mg, 0.14mmol), 1,1′-bis(diphenylphosphino)ferrocene (155 mg, 0.28 mmol) and zinc(45.7 mg, 0.698 mmol), in DMA (15 mL) was stirred for 90 min at 120° C.The reaction was cooled to RT, quenched by the addition of water andextracted with EtOAc (3×). The organic layers were combined, washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:petroleum ether to afford the title compoundI-72. ¹H NMR (400 MHz, CDCl₃) δ 8.02 (dd, J=8.0, 8.0 Hz, 1H), 7.80-7.76(m, 2H), 5.17 (s, 1H), 4.35-4.25 (m, 2H), 2.06 (s, 3H), 1.30 (t, J=7.2Hz, 3H); m/z=269 (M+1).

Intermediate 73 Ethyl3,3-dicyano-2-cyclopropyl-2-[4-(3-methoxy-2,2-dimethyl-3-oxopropyl)oxazol-2-yl]propanoate

Step A—Ethyl 3-amino-2-cyclopropyl-3-oxopropanoate

In a flask containing ethyl 2-cyano-2-cyclopropylacetate (20 g, 131mmol) and chlorotrimethylsilane (28.4 g, 261 mmol) was added water (4.7mL, 261 mmol) dropwise at 0° C. The resulting mixture was stirred for 5h at RT. The reaction mixture was divided into two layers, and thesupernatant was discarded. To this was added hexane (100 mL), and thesupernatant was discarded again. The aqueous layer was neutralised bythe addition of aq. sat. NHCO₃ at 0° C. extracted with EtOAc (3×). Theorganic layers were combined, washed with brine, dried over anhydr.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo. Theresidue was washed with hexane, and dried to afford the title compound.

Step B—Methyl3-(2-(1-cyclopropyl-2-ethoxy-2-oxoethyl)oxazol-4-yl)-2,2-dimethylpropanoate

A flask containing ethyl 3-amino-2-cyclopropyl-3-oxopropanoate (4.7 g,27.4 mmol), methyl 5-bromo-2, 2-dimethyl-4-oxopentanoate (5.0 g, 21.09mmol) and silver (I) trifluoromethanesulfonate (5.96 g, 23.20 mmol) inEtOAc (10 mL) was stirred for 16 h at 80° C. The resulting mixture wasfiltered, and the solid was washed with EtOAc. The filtrate wasconcentrated in vacuo. The residue was purified by reverse phase HPLC(ACN/water with 0.1% TFA modifier) to afford the title compound.

Step C—Methyl3-[2-(1-bromo-1-cyclopropyl-2-ethoxy-2-oxoethyl)oxazol-4-yl]-2,2-dimethylpropanoate

To a flask under an inert atmosphere of nitrogen, containing methyl3-[2-(1-cyclopropyl-2-ethoxy-2-oxoethyl)oxazol-4-yl]-2,2-dimethylpropanoate(3.4 g, 10.99 mmol) in THF (60 mL) at 0° C. was added dropwise lithiumbis(trimethylsilyl)amide (13.19 mL, 13.19 mmol, 1M in THF). Theresulting mixture was stirred 30 min at 0° C. before a solution of1-bromopyrrolidine-2, 5-dione (2.93 g, 16.49 mmol) in THF (30 mL) wasadded at 0° C. The resulting mixture was stirred for 30 min at 0° C.then quenched by the addition of aq. sat. NH₄Cl and extracted with EtOAc(3×). The organic layers were combined, washed with brine, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography withEtOAc:petroleum ether (0-10%) to afford the title compound

Step D—Ethyl3,3-dicyano-2-cyclopropyl-2-[4-(3-methoxy-2,2-dimethyl-3-oxopropyl)oxazol-2-yl]propanoate

To a flask containing methyl3-[2-(1-bromo-1-cyclopropyl-2-ethoxy-2-oxoethyl)oxazol-4-yl]-2,2-dimethylpropanoate(840 mg, 2.16 mmol) and malononitrile (858 mg, 12.98 mmol) in DMSO (5mL) at 15° C. was added potassium carbonate (897 mg, 6.49 mmol) inportions. The resulting mixture was stirred for 1.5 h at 15° C. thenquenched by the addition of aq. sat. NH₄Cl, extracted with EtOAc (3×).The organic layer was washed with brine, dried over anhydr. Na₂SO₄,filtered, and the filtrate was concentrated in vacuo. The residue waspurified by reverse phase HPLC (ACN/water with 0.05% TFA modifier) toafford the title compound I-73. ¹H NMR (300 MHz, CDCl₃) δ ¹H NMR (300MHz, CDCl₃) δ 7.44 (s, 1H), 4.67 (s, 1H), 4.33 (q, J=7.2 Hz, 2H), 3.68(s, 3H), 2.79 (s, 2H), 1.67-1.58 (m, 1H), 1.31 (t, J=7.2 Hz, 3H), 1.22(s, 3H), 1.21 (s, 3H), 0.85-0.77 (m, 2H), 0.66-0.57 (m, 2H); m/z=374(M+1).

Intermediate 74, 74A and 74B Methyl4-(1,1-dicyano-3-methoxy-2-methyl-3-oxopropan-2-yl)picolinate and the Sand R Isomers Thereof

Step A—Methyl 4-(2-methoxy-2-oxoethyl)picolinate

To a flask, under an inert atmosphere of nitrogen, containing methyl2-(2-bromopyridin-4-yl)acetate (2.0 g, 8.69 mmol), palladium(II) acetate(0.46 g, 2.09 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (2.31 g,4.17 mmol) in DMF (44 ml) was added N,N-diisopropylethylamine (7.59 ml,43.5 mmol) in MeOH (31.7 ml, 782 mmol). The flask was flushed with COand stirred 4 h under 1 atm of CO (balloon). The reaction was quenchedby the addition of EtOAc and filtered. The organic layers were combined,washed with water and brine, dried over anhydr. Na₂SO₄, and filtered.The filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography with EtOAc: hexane (0-100%) to affordthe title compound.

Step B—Methyl 4-(1-methoxy-1-oxopropan-2-yl)picolinate

To a flask, under an inert atmosphere of nitrogen, containing lithiumbis(trimethylsilyl)amide (5.26 mL, 5.26 mmol, 1M in THF) at 0° C. wasslowly added a solution of methyl 4-(2-methoxy-2-oxoethyl)picolinate(1.1 g, 5.26 mmol) in THF (10 mL), followed by methyl iodide (0.329 ml,5.26 mmol). The resulting mixture was stirred at 0° C. for 45 min thenconcentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc: hexane (0-100%) to afford the title compound.

Step C—Methyl 4-(2-bromo-1-methoxy-1-oxopropan-2-yl)picolinate

To a flask containing methyl 4-(1-methoxy-1-oxopropan-2-yl)picolinate(600 mg, 2.15 mmol) in MeCN (13 mL) was added magnesium perchlorate (316mg, 1.42 mmol). The mixture was stirred 5 min at RT beforeN-bromosuccinimide (928 mg, 5.16 mmol) was added. The mixture wasstirred at RT for 2 days, then concentrated in vacuo. The residue wasdiluted in EtOAc. The organic layers were combined, washed with water,dried over anhydr. Na₂SO₄, and filtered. The filtrate was concentratedin vacuo. The residue was purified by silica gel column chromatographywith EtOAc:hexane to afford the title compound.

Step D—Methyl4-(1,1-dicyano-3-methoxy-2-methyl-3-oxopropan-2-yl)picolinate

To a flask, under an inert atmosphere of nitrogen, containing sodiumhydride (53.7 mg, 1.34 mmol, 60% w) in DMF (5 mL) at 0° C. was addeddropwise a solution of malononitrile (89 mg, 1.343 mmol) in DMF (5 mL),followed by a solution of methyl4-(2-bromo-1-methoxy-1-oxopropan-2-yl)picolinate (390 mg, 1.03 mmol) inDMF (5 mL). The reaction was allowed to warm up to RT and stirred for 1h at RT. The reaction was quenched by the addition of aq. sat. NH₄Cl andextracted with EtOAc (3×). The organic layers were combined, washed withbrine, dried over anhydr. MgSO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:hexane (0-100%) to afford the title racemiccompound I-74. The racemic material was resolved using Chiral SFC(CHIRALPAK® IC) to afford isomer I-74A (faster eluting) and isomer I-74B(slower eluting). ¹H-NMR (400 MHz, CDCl₃): δ2.033 (s, 3H), 3.820 (s,3H), 4.015 (s, 3H), 4.539 (s, 1H), 7.454-7.478 (d, 1H), 8.103-8.108 (s,1H), 8.820-8.839 (d, 1H), m/z=288 (M+1).

Intermediate 75A Methyl3,3-dicyano-2-cyclopropyl-2-[4-(3-ethoxy-3-oxopropyl)phenyl]propanoate

Step A—Methyl 2-(4-bromophenyl)-3,3-dicyano-2-cyclopropylpropanoate

To a flask, under an inert atmosphere of nitrogen containing1,4-dibromobenzene (4.82 g, 20.43 mmol) in THF (60 mL) at −70° C. wasadded dropwise sec-butyllithium (17.0 mL, 22.14 mmol). The mixture wasstirred for 30 min at −70° C. before a solution of methyl3,3-dicyano-2-cyclopropylacrylate (3 g, 17.03 mmol) in THF (20 mL) wasadded dropwise at −70° C. The resulting mixture was stirred for 30 minat RT, then quenched by the addition of aq. sat. NH₄Cl and extractedwith EtOAc (3×). The organic layers were combined, washed with brine,dried over anhydr. Na₂SO₄, and filtered. The filtrate was concentratedin vacuo. The residue was purified by silica gel column chromatographywith EtOAc:petroleum ether (0-40%) to afford the title racemic compound.The racemic material was resolved using Chiral HPLC (CHIRALPAK® AD-H) toafford isomer A (faster eluting) and isomer B (slower eluting). ¹H NMR(400 MHz, CDCl₃) δ 7.58 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.45(s, 1H), 3.77 (s, 3H), 1.69-1.62 (m, 1H), 1.05-0.98 (m, 1H), 0.92-0.79(m, 2H), 0.53-0.47 (m, 1H); m/z=331, 333 (M−1).

Step B methyl3,3-dicyano-2-cyclopropyl-2-[4-(3-ethoxy-3-oxopropyl)phenyl]propanoate

To a flask, under an inert atmosphere of nitrogen, containing methyl2-(4-bromophenyl)-3,3-dicyano-2-cyclopropylpropanoate isomer A (300 mg,0.900 mmol) and second generation Xphos precatalyst(chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II),142 mg, 0.180 mmol) in THF (10 mL) was added(3-ethoxy-3-oxopropyl)zinc(II) bromide (10.8 mL, 5.40 mmol). Theresulting mixture was stirred at 50° C. for 6 h. The reaction wasquenched by the addition of aq. sat. NH₄Cl and extracted with EtOAc(3×). The organic layers were combined, washed with brine, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography withEtOAc:petroleum ether (0-40%) to afford the title compound I-75A. ¹H NMR(300 MHz, CDCl₃) δ 7.34 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 4.42(s, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.73 (s, 3H), 2.95 (t, J=7.8 Hz, 2H),2.61 (t, J=7.8 Hz, 2H), 1.67-1.59 (m, 1H), 1.20 (t, J=7.2 Hz, 3H),1.02-0.78 (m, 3H), 0.50-0.41 (m, 1H); m/z=353 (M−1).

Intermediate 76A Methyl(E)-3-(4-(1,1-dicyano-3-ethoxy-2-methyl-3-oxopropan-2-yl)phenyl)acrylate

A flask, under an inert atmosphere of nitrogen, containing ethyl2-(4-chlorophenyl)-3,3-dicyano-2-methylpropanoate (Intermediate 2A in WO2016/081668) (500 mg, 1.80 mmol) methyl acrylate (325 μl, 3.61 mmol),tri-tert-butylphosphonium tetrafluoroborate (52.4 mg, 0.181 mmol),tris(dibenzylideneacetone)dipalladium(0) (42.2 mg, 0.045 mmol) anddicyclohexylmethylamine (464 μl, 2.168 mmol) in dioxane (9 mL) wasstirred 2 h at 100° C. The reaction was cooled, quenched by the additionof water and extracted with EtOAc (3×). The organic layers werecombined, washed with brine, dried over anhydr. Na₂SO₄, and filtered.The filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography with EtOAc:petroleum ether (0-10%) toafford the title compound I-76A. ¹H NMR (400 MHz, CDCl₃) δ 7.67 (d,J=16.0 Hz, 1H), 7.62-7.56 (m, 2H), 7.44-7.37 (m, 2H), 6.47 (d, J=16.0Hz, 1H), 4.48 (s, 1H), 4.35-4.18 (m, 2H), 3.82 (s, 3H), 2.00 (s, 3H),1.26 (t, J=7.1 Hz, 3H). m/z=327 (M+1).

Intermediate 77 Ethyl2-{4-[3-(tert-butoxy)-3-oxopropyl]-1-(4-methoxybenzyl)-1H-imidazol-2-yl}-3,3-dicyano-2-methylpropanoate

Step A—tert-Butyl 3-(1H-imidazol-4-yl)acrylate

To a flask containing 1H-imidazole-4-carbaldehyde (10 g, 104 mmol) andtert-butyl 2-(diethoxyphosphoryl)acetate (39.4 g, 156 mmol) in DMF (100mL) at 0° C. was added in portions sodium hydride (4.99 g, 208 mmol, 60%w). The resulting mixture was stirred for 3 h at 95° C. then cooled toRT and quenched by the addition of aq. sat. NaHCO₃ and extracted withEtOAc (3×). The organic layers were combined, washed with water andbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:petroleum ether (0-80%) to afford the titlecompound.

Step B—tert-Butyl 3-(1-(4-methoxybenzyl)-1H-imidazol-4-yl)acrylate

To a flask containing tert-butyl 3-(1H-imidazol-4-yl)acrylate (9.3 g,43.1 mmol) and potassium carbonate (11.9 g, 86 mmol) in DMF (100 mL) at0° C. was added dropwise 1-(chloromethyl)-4-methoxybenzene (10.1 g, 64.6mmol). The resulting mixture was stirred for 2 h at RT then quenched bythe addition of water and extracted with EtOAc (3×). The organic layerswere combined, washed with water and brine, dried over anhydr. Na₂SO₄,and filtered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography with EtOAc:petroleum ether(10-60%) to afford the title compound.

Step C—tert-Butyl 3-[1-(4-methoxybenzyl)-1H-imidazol-4-yl]propanoate

To a flask containing tert-butyl3-(1-(4-methoxybenzyl)-1H-imidazol-4-yl)acrylate (10 g, 31.8 mmol) inMeOH (100 mL) was added palladium on carbon (wet, 1.5 g, 10%) at RT. Theflask was evacuated and flushed three times with nitrogen, followed byflushing with hydrogen. The mixture was stirred 4 h at RT under anatmosphere of hydrogen (1.5 atm). The mixture was filtered and theresidue rinsed with MeOH. The filtrate was concentrated in vacuo toafford the title compound.

Step D—tert-Butyl3-[2-(2-ethoxy-2-oxoacetyl)-1-(4-methoxybenzyl)-1H-imidazol-4-yl]propanoate

To a flask containing tert-butyl3-[1-(4-methoxybenzyl)-1H-imidazol-4-yl]propanoate (8.5 g, 26.9 mmol) inDCM (100 mL) at −40° C. was added dropwise ethyl 2-chloro-2-oxoacetate(11.0 g, 81 mmol) followed by the dropwise addition ofN-ethyl-N-isopropylpropan-2-amine (10.4 g, 81 mmol) at −40° C. Themixture was stirred for 6 h at RT then quenched by the addition of aq.sat. NaHCO₃ and extracted with DCM (3×). The organic layers werecombined, washed with brine, dried over anhydr. Na₂SO₄, and filtered.The filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography with EtOAc:petroleum ether (10-60%) toafford the title compound.

Step E—Ethyl2-[4-(3-tert-butoxy-3-oxopropyl)-1-(4-methoxybenzyl)-1H-imidazol-2-yl]-3,3-dicyanoacrylate

To a flask containing tert-butyl3-[2-(2-ethoxy-2-oxoacetyl)-1-(4-methoxybenzyl)-1H-imidazol-4-yl]propanoate(2.0 g, 4.80 mmol), malononitrile (1.59 g, 24.01 mmol) in chloroform (20mL) at RT was added aluminium oxide (4.9 g, 48.0 mmol). The resultingmixture was stirred for 2 h at RT then filtered, and the residue rinsedwith DCM. The filtrate was diluted with aq. sat. NH₄Cl and extractedwith DCM (3×). The organic layers were combined, washed with brine,dried over anhydr. Na₂SO₄, and filtered. The filtrate was concentratedin vacuo. The residue was purified by silica gel column chromatographywith EtOAc:petroleum ether (10-60%) to afford the title compound.

Step F—Ethyl2-{4-[3-(tert-butoxy)-3-oxopropyl]-1-(4-methoxybenzyl)-1H-imidazol-2-yl}-3,3-dicyano-2-methylpropanoate

A flask, under an inert atmosphere of nitrogen, containing ethyl2-{4-[3-(tert-butoxy)-3-oxopropyl]-1-(4-methoxybenzyl)-1H-imidazol-2-yl}-3,3-dicyanoacrylate(550 mg, 1.18 mmol) and lithium chloride (100 mg, 2.37 mmol) in THF (10mL) was stirred 30 min at 0° C. before methylmagnesium chloride (0.51mL, 1.54 mmol, 3M in THF) was added dropwise at 0° C. The mixture wasstirred for 2 h at 0° C., then quenched by the addition of aq. sat.NH₄Cl and extracted with EtOAc (3×). The organic layers were combined,washed with brine, dried over anhydr. Na₂SO₄, and filtered. The filtratewas concentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:petroleum ether (0-50%) to afford the titlecompound I-77. ¹H NMR (300 MHz, CDCl₃) δ 6.97 (d, J=8.7 Hz, 2H), 6.89(d, J=8.7 Hz, 2H), 6.55 (s, 1H), 5.22 (s, 1H), 5.05 (s, 2H), 4.29-4.09(m, 2H), 3.82 (s, 3H), 2.82 (t, J=7.2 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H),1.98 (s, 3H), 1.41 (s, 9H), 1.28 (t, J=7.2 Hz, 3H); m/z=479 (M−1).

Intermediate 78A Ethyl2-(4-(2-(tert-butoxy)-2-oxoethyl)phenyl)-3,3-dicyano-2-methylpropanoate

A microwave vial, under an inert atmosphere of nitrogen, containingI-21A (500 mg, 1.56 mmol), (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide(4.05 g, 15.57 mmol), tetrakis(dibenzylideneacetone)dipalladium (179 mg,0.16 mmol) and tri-tert-butylphosphonium tetrafluoroborate (181 mg, 0.62mmol) in THF (15 mL) was stirred for 1 h at RT and then irradiated withmicrowave radiation for 1 h at 120° C. The reaction was quenched by theaddition of aq. sat. NH₄Cl and extracted with EtOAc (3×). The organiclayers were combined, washed with brine, dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography with EtOAc:petroleum ether(0-20%) to afford the title compound I-78A. ¹H NMR (400 MHz, CD₃OD),7.41-7.33 (m, 4H), 4.86 (s, 1H), 4.27 (q, J=7.2 Hz, 2H), 3.57 (s, 2H),1.93 (s, 3H), 1.42 (s, 9H), 1.23 (t, J=7.2 Hz, 3H); m/z=355 (M−1).

Intermediate A16-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazole-3-carboximidamide

Step A—6-chloro-1H-indazole

Acetic anhydride (10.0 mL, 106 mmol) was added dropwise to a benzenesolution (110 mL) containing 5-chloro-2-methylaniline (5.0 g, 35.3 mmol)and potassium acetate (3.8 g, 38.7 mmol) at RT. After 10 minutes thereaction mixture was heated to 80° C. tert-butyl nitrite (6.99 mL, 90%,53.0 mmol) was added over 20 minutes. The reaction mixture was kept at80° C. overnight, then cooled to RT and concentrated. The residue wasdissolved in MeOH and stirred for 10 minutes. The solution wasconcentrated and to the residue was added MeOH (175 mL), THF (30 mL),water (60 mL) and LiOH monohydrate (8 g, 195 mmol). The solution wasthen stirred overnight at RT. The solution was then concentrated and theresidue partitioned between EtOAc and 0.5 M NaOH aq. The aqueous phasewas extracted with EtOAc (2×). The combined organics were washed withbrine, dried over MgSO₄, filtered and concentrated to give the indicatedproduct. The material was used in Step B without further purification.¹H NMR (400 MHz, CH₃CN-d₃): δ 11.20 (br s, 1H); 8.01 (s, 1H); 7.75-7.70(m, 1H); 7.60 (s, 1H); 7.13 (dd, J=8.6, 1.7 Hz, 1H). m/z=153 (M+1).

Step A Alternative-6-chloro-1H-indazole

A DMA (250 mL) solution containing 4-chloro-2-fluorobenzaldehyde (50 g,315 mmol) and hydrazine monohydrate (230 mL, 4730 mmol) was stirred for30 minutes at RT. The solution was then stirred at 100° C. for 17 hours.The reaction mixture, which was a thick white slurry, was cooled to RT.The solid was collected by filtration, washed with water and dried undervacuum to give the title product.

Step B—6-chloro-3-iodo-1H-indazole

An MeCN solution (250 mL) containing the intermediate from Step A (6.14g, 40.2 mmol) and NIS (9.33 g, 41.4 mmol) was heated at 60° C. for 3hours. The reaction solution was cooled to RT and concentrated toapproximately 70 mL volume. The reaction was then diluted with water,the suspension was stirred for 10 minutes and then filtered. The solidwas air dried on the filter to give the indicated product. The materialwas used in Step C without further purification. ¹H NMR (400 MHz,CH₃CN-d₃): δ 1.52 (br s, 1H); 7.62 (d, J=1.7 Hz, 1H); 7.44 (d, J=8.6 Hz,1H); 7.21 (dd, J=8.6, 1.7 Hz, 1H). m/z=279.0 (M+1).

Step C—6-chloro-1H-indazole-3-carbonitrile

A DMA (48 mL) solution containing the intermediate from Step B (4.0 g,14.36 mmol), zinc powder (113 mg, 1.72 mmol), zinc cyanide (1.01 g, 8.86mmol), 1,1′-bis(diphenylphosphino)ferrocene (318 mg, 0.58 mmol) andtris(dibenzylideneacetone)dipalladium (263 mg, 0.29 mmol) was heated at120° C. for 45 minutes. The solution was cooled to RT and partitionedbetween EtOAc and 0.5M HCl aq. The organic phase was washed twice with0.5M aq. HCl and brine. The organic phase was then dried over MgSO₄,filtered and concentrated. The crude material was purified by silica gelchromatography using a hexanes/EtOAc gradient to give the indicatedproduct. ¹H NMR (400 MHz, CH₃CN-d₃): δ 7.83 (d, J=8.7 Hz, 1H); 7.77 (d,J=1.7 Hz, 1H); 7.36 (dd, J=8.7, 1.7 Hz, 1H); m/z=178.1 (M+1).

StepD—6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazole-3-carbonitrile

An acetonitrile solution (450 mL) containing the intermediate from StepC (30 g, 169 mmol), potassium carbonate (116.6 g, 844 mmol) and1,1,1,2,2-pentafluoro-4-iodobutane (97.2 g, 354.7 mmol) was refluxed for36 hours. The solution was cooled to RT and partitioned between EtOAcand water. The organic phase was concentrated and the crude material wasfiltered through a plug of silica gel using 10% EtOAc/heptanes as theeluent. The isolated material was subsequently recrystallized fromheptanes to give the indicated product. ¹H NMR (400 MHz, CH₃CN-d₃): δ7.87-7.80 (m, 2H); 7.40 (dd, J=8.7, 1.7 Hz, 1H); 4.77 (t, J=7.0 Hz, 2H);2.95-2.78 (m, 2H). m/z=324.1 (M+1).

StepE—6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazole-3-carboximidamide

Trimethylaluminum (23.17 mL, 46.3 mmol, 2.0 M in toluene) was addeddropwise to a suspension of ammonium chloride (2.49 g, 46.5 mmol) in 69mL toluene at 0° C. The solution was stirred at RT for 3 hours, thenadded to the intermediate from Step D (3.0 g, 9.27 mmol) and heated at110° C. for 6 hours. The mixture was cooled to RT and poured to amixture of silica gel and MeOH. After stirring for 1.5 h the suspensionwas filtered and the filtrate concentrated to give I-A1. ¹H NMR (400MHz, CH₃CN-d₃): δ 8.26 (d, J=8.7 Hz, 1H); 7.70 (d, J=1.7 Hz, 1H); 7.24(dd, J=8.7, 1.8 Hz, 1H); 4.67 (t, J=7.1 Hz, 2H); 3.01-2.78 (m, 2H);m/z=341.1 (M+1).

Intermediate A21-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide

StepA—1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

In a flask containing 1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (5 g,34.7 mmol) in acetonitrile (75 mL) was added1,1,1,2,2-pentafluoro-4-iodobutane (9.82 mL, 69.4 mmol) and potassiumcarbonate (24.0 g, 173 mmol). The reaction was stirred at 45° C. for 18hours then cooled to RT, diluted with water and extracted with EtOAc(3×). The organic layers were combined, dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography with EtOAc:Hex (0-100%) toafford the title compound.

StepB—1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide

In a flask containing1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile(5.1 g, 17.7 mmol) in MeOH (11 mL) at RT was added NaOMe (1.34 g, 24.7mmol). The mixture was stirred at RT for 3 h before acetic acid (4.05mL, 70.7 mmol) was added, followed by ammonium chloride (1.23 g, 23.0mmol). The resulting slurry was heated to 65° C. for 4 h then cooled toRT, quenched by the addition of aq. sat. NaHCO₃ and extracted with EtOAc(3×). The organic layers were combined, washed with brine, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography with(EtOAc:MeOH 10:1):hexane gradient to afford the title compound I-A2. ¹HNMR (400 MHz, DMSO-d₆) δ 9.45 (s, 3H), 8.77 (dd, J=4.5, 1.5 Hz, 1H),8.56 (dd, J=8.3, 1.5 Hz, 1H), 7.53 (dd, J=8.3, 4.5 Hz, 1H), 4.93 (t,J=6.8 Hz, 2H), 3.06 (tt, J=19.1, 6.9 Hz, 2H); m/z=308 (M+1).

Using a similar procedure to that described in the preparation ofIntermediate A1 and A2, the following compounds in Table 10 wereprepared from commercial starting reagents or compounds known in theliterature.

TABLE 10

Int. X R^(2s) R^(1b) R^(1a) m/z (M + 1) I-A3 N

F H 276 I-A4 N

F H 326 I-A5 C(H)

H Cl 251 I-A6 N

H H 218 I-A7 C(H)

H Cl 253 I-A8 C(H)

H Cl 305 I-A9 N

H H 272 I-A10 N

F H 290 I-A11 C(H)

H Cl 265 I-A12 C(H)

H Cl 291 I-A13 C(H)

H Cl 279 I-A14 C(H)

H F 325 I-A15 C(H)

H Cl 303 I-A16 N

H H 270 I-A17 C(H)

H Cl 293 I-A18 N

F H 288 I-A19 C(H)

H Cl 305 I-A20 C(H)

H Cl 304 I-A21 C(H)

H Cl 293 I-A22 C(H)

H Cl 327 I-A23 C(H)

H F 287 I-A24 C(H)

OMe Cl 333 I-A25 C(H)

H Me 283 I-A26 C(H)

H Cl 343 I-A27 C(H)

H Cl 303 I-A28 C(H)

H Cl 303 I-A29 C(H)

H Cl 321 I-A30 C(H)

H Cl 299 I-A31 C(H)

H Cl 299 I-A32 C(H)

H Cl 299 I-A33 C(H)

F H 287 I-A34 C(H)

Cl H 303

Intermediate A356-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide

StepA—1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

Using essentially the same procedures described in I-A1 steps C and D,the title compound was prepared, using 3-iodo-1H-pyrazolo[3,4-b]pyridineas starting material. m/z=291 (M+1).

Step B—3-cyano-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine7-oxide

In a flask containing1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile(6.3 g, 21.8 mmol) and 3-chloroperbenzoic acid (22 g, 98 mmol) was addedacetic acid (50 mL). The resulting mixture was stirred at 80° C. for 8 hbefore the mixture was cooled to RT and concentrated in vacuo todryness. The residue was dissolved in 250 mL of a 2:1 mixture ofHexane:EtOAc and the pH was adjusted to pH 7 by addition of a sat. aq.K₂CO₃. The resulting solution was extracted with EtOAc (3×) and theorganic layers were combined, washed with brine, dried over anhydr.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo to dryness.The residue purified by silica gel chromatography with EtOAc:petroleumether:NH₃ (2M in MeOH) (0-20%) to afford the title compound. m/z=307(M+1).

StepC—6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

In a flask containing3-cyano-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine7-oxide (1.9 g, 1.2 mmol) was added Phosphorus (V) oxychloride (6.9 mL,74 mmol). The resulting mixture was stirred at 80° C. for 5 h. Themixture was diluted in 250 mL of a 2:1 mixture of Hexane:EtOAc and thepH was adjusted to pH 7 by addition of a sat. aq. K₂CO₃. The resultingsolution was extracted with a 2:1 mixture of hexane:EtOAc (3×). Theorganic layers were combined, dried over anhydr. Na₂SO₄, and filtered.The filtrate was concentrated in vacuo to dryness. The residue waspurified by silica gel chromatography with EtOAc:petroleum ether toafford the title compound. m/z=325 (M+1).

StepD—6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide

Trimethylaluminum (19.9 mL, 39.8 mmol, 2.0 M in toluene) was addeddropwise to a suspension of ammonium chloride (2.1 g, 39.8 mmol) in 24mL toluene at 0° C. The solution was then stirred at RT for 3 hours thenadded to6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile(2.6 g, 8.0 mmol) and heated at 75° C. overnight. The reaction mixturewas cooled to RT, and quenched by the addition of MeOH:DCM (1:1) andsilica. After stirring for 3 hours the suspension was filtered throughdiatomaceous earth and the filtrate was concentrated in vacuo dryness toafford the title compound I-A35. ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (d,J=8.4 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 6.68 (br, 3H), 4.76 (t, J=7.2 Hz,2H), 3.07-2.93 (m, 2H); m/z=342 (M+1).

Using a similar procedure to that described in the preparation ofIntermediate I-A35, the following compounds in Table 7 were preparedfrom commercial starting reagents or compounds known in the literature.

TABLE 11

Int. R^(2s) m/z (M + 1) I-A36

252 I-A37

306

Intermediate A386-Methyl-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide

StepA—6-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

Using essentially the same procedures described in intermediate I-35step A to C, the title compound was prepared. ¹H NMR (300 MHz, CDCl₃) δ8.16 (d, J=8.5 Hz, 1H), 7.38 (d, J=8.5 Hz, 1H), 4.65 (t, J=6.6 Hz, 2H),2.38-2.09 (m, 4H); m/z=288 (M+1).

StepB—6-methyl-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile

To a solution containing6-chloro-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile(800 mg, 2.77 mmol) in THF (10 mL) was addedbis(triphenylphosphine)palladium(II) dichloride (195 mg, 0.28 mmol) theresulting solution was stirred at RT for 30 min. Dimethylzinc (8.31 mL,8.31 mmol, 1 M in THF) was added and the resulting mixture was stirred16 hours at RT. The reaction was quenched by the addition of aq. sat.NH₄Cl, extracted with EtOAc (3×). The organic layer was washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:petroleum ether (0-30%) to afford the titlecompound. m/z=269 (M+1).

StepC—6-methyl-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide

Trimethylaluminum (4.0 mL, 8.0 mmol, 2.0 M in toluene) was addeddropwise to a suspension of ammonium chloride (570 mg, 10.6 mmol) in 10mL toluene cooled to 0° C. The solution was then stirred at RT for 1hours. To this solution was added6-methyl-1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile(270 mg, 1.00 mmol) and the resulting mixture was heated at 100° C. for2 h. The reaction mixture was cooled to 0° C., and quenched by theaddition of a MeOH:DCM (1:1) mixture. After stirring for 1 hour thesuspension was filtered through diatomaceous earth and the filtrate wasconcentrated in vacuo dryness. The residue was diluted in EtOAc and thepH was adjusted to pH 10 by addition of 1 M NaOH (aqueous solution). Theresulting solution was extracted with EtOAc (3×). The organic layer waswashed with brine, dried over anhydr. Na₂SO₄, and filtered. The filtratewas concentrated in vacuo to afford the title compound I-A38. H NMR (300MHz, DMSO-d₆) δ 8.50 (d, J=8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.48(br, 3H), 4.52 (t, J=7.2 Hz, 2H), 2.61 (s, 3H), 2.45-2.28 (m, 2H),2.16-2.06 (m, 2H); m/z=286 (M+1).

Intermediate A391-(2,3-difluoro-4-methylbenzyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide

The title compound was prepared using the protocol published in WO2015-004105-A1.

Intermediate A40 1-(2-fluorobenzyl)-1H-indazole-3-carboximidamide

A flask under nitrogen containing I-A15 (1.0 g, 2.95 mmol) and palladiumon carbon (1.0 g, 10 w %) in MeOH (50 mL), was purged with hydrogen. Themixture was stirred at RT for 0.5 h under an atmosphere of hydrogen (˜2atm). The solid was filtered out and washed with MeOH (3×). The filtratewas concentrated in vacuo to dryness. The residue was purified by C18column chromatography with acetonitrile:water: 0.1% trifluoroaceticacid, (20%-40%) to afford the title compound I-A40. ¹H NMR (400 MHz,DMSO-d₆) δ 9.40-9.30 (br, 4H), 8.04 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.4Hz, 1H), 7.64-7.59 (m, 1H), 7.47-7.37 (m, 2H), 7.28-7.23 (m, 2H),7.21-7.16 (m, 1H), 5.92 (s, 2H); m/z=269 (M+1).

Intermediate A416-Chloro-1-(cyclopentylmethyl)-1H-indazole-3-carboximidamide

Step A—6-Chloro-1-(cyclopentylmethyl)-1H-indazole-3-carbonitrile

To a flask containing 6-chloro-1H-indazole-3-carbonitrile (1.0 g, 5.63mmol) and cyclopentylmethyl 4-methylbenzenesulfonate (1.9 g, 7.32 mmol)in DMF (10 mL), was added potassium phosphate (2.4 g, 11.26 mmol) andthe resulting mixture was stirred for 16 h at 70° C. The reaction wascooled to RT, quenched by the addition of brine, and extracted withEtOAc (3×). The organic layer was washed with brine, dried over anhydr.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography withEtOAc:petroleum ether (0-10%) to afford the title compound. m/z=301(M+1).

Step B—6-Chloro-1-(cyclopentylmethyl)-1H-indazole-3-carboximidamide

To a flask, under a inert atmosphere of nitrogen, containing6-chloro-1-(cyclopentylmethyl)-1H-indazole-3-carbonitrile (1.0 g, 3.85mmol) in MeOH (10 mL) was added NaOMe (0.42 g, 7.70 mmol). The solutionwas stirred for 2 h at RT and ammonium chloride (0.62 g, 11.55 mmol) wasadded. The resulting mixture was stirred for 3 h at 7° C. The mixturewas cooled to RT and concentrated in vacuo to dryness. The residue waspoured into water (100 mL). 2N HCl solution was added to reach pH 1˜2,the resulting solution was extracted with Et₂O (2×) and the aqueouslayer was kept. Then the pH value of the aqueous layer was adjusted to11-12 with NaOH (1 N). The resulting aqueous solution was extracted withEtOAc (3×), The organic layer was dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo to afford the titlecompound I-A41. ¹H NMR (300 MHz, CD₃OD) δ 8.08 (d, J=8.7 Hz, 1H), 8.68(d, J=1.8 Hz, 1H), 7.18 (dd, J=8.7, 1.8 Hz, 1H), 4.31 (d, J=7.5 Hz, 2H),2.57-2.48 (m, 1H), 1.73-1.47 (m, 6H), 1.39-1.21 (m, 2H); m/z=277 (M+1).

Using a similar procedure to that described in the preparation ofIntermediate A1, I-A2 and I-A41 the following compounds in Table 12 wereprepared from commercial starting reagents or compounds known in theliterature.

TABLE 12

m/z Int. X R2s R1b R1a (M + 1) I-A42 C(H)

H Cl 321 I-A43 C(H)

H Cl 321 I-A44 C(H)

H Cl 339 I-A45 C(H)

H Cl 317 I-A46 C(H)

H F 301 I-A47 C(H)

H Cl 317 I-A48 C(H)

H F 277 I-A49 C(H)

H F 287 1-A50 C(H)

H F 305 I-A51 N

H H 270 I-A52 N

H H 258 I-A53 C(H)

H Cl 299 I-A54 C(H)

H F 275 I-A55 C(H)

H F 289 I-A56 N

H H 244 I-A57 N

H H 260 I-A58 N

H H 272 I-A59 N

H H 246 I-A60 C(H)

H Cl 279 I-A61 C(H)

H H 270 I-A62 C(H)

H Cl 318

Example 1A3-(2-{4-Amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoicacid

Step A—methyl3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoate

Into a flask was placed I-A16 (200 mg, 0.74 mmol), I-32 (258 mg, 0.74mmol), potassium bicarbonate (112 mg, 1.11 mmol) and t-BuOH (10 mL). Theresulting mixture was stirred at 80° C. for 16 h then concentrated invacuo to dryness. The residue was purified by silica gel chromatographyusing (MeOH:DCM) to afford the racemic title product. The racemicmaterial was resolved using Chiral SFC (CHIRALPAK® AD-H) to affordisomer A (faster eluting) and isomer B (slower eluting). m/z=571 (M+1).

StepB—3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoicacid

To a flask containing methyl3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4-yl)-2,2-dimethylpropanoateisomer A (160 mg, 0.280 mmol) in MeOH (5 mL) was added LiOH (67 mg, 2.80mmol) in 1 mL of water. The resulting mixture was stirred 48 h at RT.The reaction was concentrated in vacuo to dryness. The residue wasdiluted with concentrated sat. Na₂CO₃ and extracted with EtOAc (3×). ThepH of the aqueous phase was adjusted to pH 6 with HCl (1M) the resultingsolid was collected by filtration, washed with water, and dried undervacuum to afford the title product Ex-1A. ¹H NMR (300 MHz, CD₃OD) δ 9.06(d, J=7.8 Hz, 1H), 8.61 (dd, J=4.5, 1.5 Hz, 1H), 7.63 (s, 1H), 7.40-7.27(m, 2H), 7.16-7.06 (m, 3H), 5.91 (s, 2H), 2.86-2.72 (m, 2H), 1.92 (s,3H), 1.23 (s, 3H), 1.19 (s, 3H); m/z=557 (M+1).

Using essentially the same procedure described in Ex-1A, the followingcompounds in Table 13 were prepared.

TABLE 13 Chiral Int. Resolution m/z Ex. SM Column Structure Name (M + 1)2A I-32 IA

3-(2-{4-amino-2-[6- chloro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5- methyl-6-oxo-6,7- dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl}oxazol-4-yl)-2,2- dimethylpropanoic acid 628 3A I-32IA

3-(2-{4-amino-2-[6- chloro-1-(2- fluorobenzyl)-1H- indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H- pyrrolo[2,3- d]pyrimidin-5-yl)oxazol-4-yl}-2,2- dimethylpropanoic acid 590 4B I-14 (R,R)WHELK- 01

3-(4-{4-amino-2-[6- chloro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5- methyl-6-oxo-6,7- dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-2- bromophenyl)propanoic acid 689 5BA I-11B IA

(5S)-3-{4-[4-amino-2- {6-chloro-1-[(4- methylcyclohexyl)methyl]-1H-indazol-3-yl}- 5-methyl-6-oxo-6,7- dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl]phenyl}propanoic acid 573 5BB I-11B IA

(5S)-3-{4-[4-amino-2- {6-chloro-1-[(4- methylcyclohexyl)methyl]-1H-indazol-3-yl}- 5-methyl-6-oxo-6,7- dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl]phenyl}propanoic acid 573 6BA I-11B IC

(5S)-3-{4-[4-amino-2- {6-chloro-1- [tetrahydro-2H-pyran- 2-ylmethyl]-1H-indazol-3-yl}-5- methyl-6-oxo-6,7- dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl]phenyl}propanoic acid 561 7A I-11 AD

(S)-3-(4-{4-amino-5- methyl-6-oxo-2-[1- (3,3,4,4,4-pentafluorobutyl)-1H- pyrazolo[3,4-b]pyridin- 3-yl]-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanoic acid 576 8B I-20 IC

3-(6-{4-amino-5- methyl-6-oxo-2-[1- (3,3,4,4,4- pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin- 3-yl]-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl}pyridin-3-yl)-2,2- dimethylpropanoic acid 638 ¹H NMRData 2A ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 11.39 (s, 1H), 8.68(d, J = 8.7 Hz, 1H), 8.04 (d, J = 1.7 Hz, 1H), 7.75 (s, 1H), 7.28 (dd, J= 8.7, 1.7 Hz, 1H), 6.65 (s, 2H), 4.84 (t, J = 6.9 Hz, 2H), 2.91 (tt, J= 19.4, 6.9 Hz, 2H), 2.76-2.56 (m, 2H), 1.81 (s, 3H), 1.10 (s, 3H), 1.08(s, 3H) 3A ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 11.37 (s, 1H),8.69 (d, J = 8.7 Hz, 1H), 8.01 (d, J = 1.7 Hz, 1H), 7.74 (s, 1H),7.42-7.11 (m, 5H), 6.64 (s, 2H), 5.81 (s, 2H), 2.71- 2.57 (m, 2H), 1.80(s, 3H), 1.09 (d, J = 8.7 Hz, 6H) 4B ¹H NMR (300 MHz, CD₃OD) δ 8.70 (d,J = 8.7 Hz, 1H), 7.77 (s, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.41-7.21 (m,3H), 4.83 (t, J = 7.2 Hz, 2H), 3.12-2.84 (m, 4H), 2.66-2.45 (m, 2H),1.87 (s, 3H) 5BA ¹H NMR (300 MHz, CD₃OD) δ 8.66 (d, J = 9.0 Hz, 1H),7.70 (s, 1H), 7.34-7.21 (m, 5H), 4.42 (d, J = 7.5 Hz, 2H), 2.91 (t, J =7.5 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.33-2.21 (m, 1H), 1.87 (s, 3H),1.69-1.67 (m, 1H), 1.55-1.43 (m. 8H), 1.00 (d, J = 6.9 Hz, 3H) 5BB ¹HNMR (300 MHz, CD₃OD) δ 8.66 (d, J = 8.7 Hz, 1H), 7.69 (s, 1H), 7.31-7.21(m, 5H), 4.31 (d, J = 7.2 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H), 2.57 (t, J= 7.5 Hz, 2H), 2.09-1.95 (m, 1H), 1.87 (s, 3H), 1.72-1.69 (m, 2H),1.61-1.57 (m, 2H), 1.43-1.29 (m, 1H), 1.21-1.09 (m, 2H), 0.96-0.88 (m,5H) 6BA ¹H NMR (300 MHz, CD₃OD) δ 8.61 (d, J = 8.7 Hz, 1H), 7.68 (d, J =0.9 Hz, 1H), 7.30-7.17 (m, 5H), 4.52-4.38 (m, 2H), 3.88-3.84 (m, 2H),3.36-3.28 (m, 1H), 2.88 (t, J = 7.5 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H),1.89-1.80 (m, 4H), 1.68-1.64 (m, 1H), 1.57-1.30 (m, 4H) 7A ¹H NMR (500MHz, CD₃OD) δ 9.07 (dd, J = 8.1, 1.6 Hz, 1H), 8.64 (dd, J = 4.6, 1.6 Hz,1H), 7.38 (dd, J = 8.1, 4.6 Hz, 1H), 7.35-7.21 (m, 4H), 4.98 (t, J = 7.3Hz, 2H), 3.01 (td, J = 18.4, 9.2 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.61(t, J = 7.6 Hz, 2H), 1.90 (s, 3H) 8B ¹H NMR (CD₃OD, 300 MHz) δ 8.60 (d,J = 9.0 Hz, 1H), 8.45 (s, 1H), 7.84 (s, 1H), 7.71 (dd, J = 8.1, 2.1 Hz,1H), 7.49 (d, J = 8.4 Hz, 1H), 7.32 (dd, J = 8.7, 1.5 Hz, 1H), 4.88-4.83(m, 2H), 3.09-2.87 (m, 4H), 1.93 (s, 3H), 1.20 (s, 6H)

Example 9B3-(4-{4-Amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoicacid

Step A—methyl3-(4-{4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoate

Into a flask was placed I-13B (50 mg, 0.14 mmol), I-A2 (48 mg, 0.14mmol), potassium bicarbonate (42 mg, 0.42 mmol) and t-BuOH (1.4 mL). Theresulting mixture was warmed at 65° C. for 16 h. The reaction was cooledto RT and quenched by the addition of water. The resulting solution wasextracted with EtOAc (3×) and the organic layers were combined, driedover anhydr. Na₂SO₄, filtered and the filtrate was concentrated in vacuoto dryness. The residue was purified by silica gel chromatography using(EtOAc: EtOH 3:1):hexane gradient to afford the title product. m/z=618.2(M+1).

StepB—3-(4-{4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoicacid

Into a flask was placed methyl3-(4-{4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-2,3-dihydro-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoate(61 mg, 0.10 mmol), LiOH (24 mg, 0.98 mmol), dioxane (2.5 mL) and water(2.5 mL). The resulting mixture was warmed at 65° C. for 16 h. Thereaction was cooled to RT and quenched by the addition of acetic acid(73 μL, 1.3 mmol). The resulting solution was extracted with EtOAc (3×),the organic layers were combined, dried over anhydr. MgSO₄, filtered andthe filtrate was concentrated in vacuo to dryness. The residue waspurified by silica gel chromatography using (EtOAc: EtOH 3:1):hexanegradient to afford the title product Ex-9B. ¹H NMR (400 MHz, DMSO-d₆) δ12.24 (s, 1H), 11.11 (s, 1H), 9.03 (dd, J=8.1, 1.6 Hz, 1H), 8.63 (dd,J=4.5, 1.6 Hz, 1H), 7.37 (dd, J=8.1, 4.5 Hz, 1H), 7.17 (d, J=8.4 Hz,2H), 7.11 (d, J=8.3 Hz, 2H), 6.56 (s, 2H), 4.87 (t, J=6.8 Hz, 2H), 2.97(tt, J=19.1, 6.8 Hz, 2H), 2.74 (s, 2H), 1.77 (s, 3H), 1.04 (s, 6H);m/z=604 (M+1)

Example 10B(S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoicacid

Step A—(S)-Methyl3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoate

In a flask containing I-A1 (91 mg, 0.27 mmol), I-11B (80 mg, 0.24 mmol)and potassium bicarbonate (73.2 mg, 0.73 mmol) in t-BuOH (2.4 mL) wasstirred at 80° C. for 16 h. The reaction was cooled to RT, diluted withEtOAc and water, and extracted with EtOAc (3×). The organic layers werecombined, washed with brine, dried over anhydr. Na₂SO₄, and filtered.The filtrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography with (EtOAc:EtOH 3:1):hexane (0-40%) toafford the title compound. m/z=623 (M+1).

StepB—(S)-3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoicacid

In a flask containing (S)-methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoate(120 mg, 0.19 mmol) in dioxane (8.7 mL) was added LiOH (46 mg, 1.93mmol) in water (1 mL). The reaction was stirred 2 h at 50° C. Thereaction was cooled to RT, concentrated in vacuo and diluted with EtOAc.Acetic acid (132 μl, 2.31 mmol) was added and the mixture was extractedwith EtOAc (3×). The organic layers were combined, washed with brine(2×), dried over anhydr. MgSO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with (EtOAc:EtOH 3:1):hexane (0-100%) to afford the titlecompound Ex-10B. ¹H NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 1H), 11.09 (s,1H), 8.69 (d, J=8.7 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H), 7.26 (dd, J=8.7,1.7 Hz, 1H), 7.22-7.11 (m, 4H), 6.54 (s, 2H), 4.82 (t, J=6.8 Hz, 2H),2.90 (tt, J=19.4, 6.9 Hz, 2H), 2.77 (t, J=7.6 Hz, 2H), 2.52-2.49 (m,2H), 1.76 (s, 3H); m/z=609 (M+1).

Example 11B3-(3-{4-Amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoicacid

Step A—methyl3-(3-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylPropanoate

To a flask containing intermediate A2 (45.6 mg, 0.15 mmol) and I-39B (50mg, 0.14 mmol) in THF (2.7 mL) was added triethylamine (56 μl, 0.40mmol). The resulting mixture was stirred at 80° C. for 6 h then 24 h at60° C. The reaction was cooled to RT diluted with EtOAc and water. Theresulting mixture was extracted with EtOAc (3×), the organic layers werecombined, washed with brine, dried over anhydr. MgSO₄, filtered and thefiltrate was concentrated in vacuo to dryness. The residue was purifiedby silica gel chromatography using (EtOAc:EtOH 3:1):hexane (0-40%) toafford the title compound. m/z=632 (M+1).

StepB—3-(3-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoicacid

To a flask containing methyl3-(3-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2-dimethylpropanoate (80 mg, 0.13 mmol) in a dioxane (5.8 mL) water (0.6 mL)mixture was added LiOH (30 mg, 1.28 mmol) the resulting mixture wasstirred at 80° C. for 16 h. The reaction was cooled to RT, diluted withEtOAc and water, and quenched by the addition of acetic acid (87 μl,1.52 mmol). The resulting solution was extracted with EtOAc (3×) and theorganic layers were combined, washed with brine dried over anhydr.MgSO₄, filtered and the filtrate was concentrated in vacuo to dryness.The residue was purified by silica gel chromatography using (EtOAc:EtOH3:1):hexane (10%-70%) to afford the title compound Ex-11B. ¹H NMR (500MHz, MeOD) δ 9.03 (dd, J=8.1, 1.6 Hz, 1H), 8.60 (dd, J=4.5, 1.6 Hz, 1H),7.35 (dd, J=8.1, 4.5 Hz, 1H), 7.30-7.18 (m, 3H), 7.18-7.11 (m, 1H), 4.95(t, J=7.3 Hz, 2H), 3.05-2.93 (m, 2H), 2.91 (d, J=13.2 Hz, 1H), 2.79 (d,J=13.2 Hz, 1H), 1.88 (s, 3H), 1.18 (s, 3H), 1.10 (s, 3H); m/z=604 (M+1).

Using essentially the same procedure described in examples 9, 10 and 11,the following compounds in Table 14 were prepared.

TABLE 14 Int. m/z Ex. SM Structure Name (M + 1) 12B I-24B

3-(4-{4-amino-5-methyl-6- oxo-2-[1-(3,3,4,4,4- pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3- triazol-1-yl)propanoic acid 567 13B I-11B

(S)-3-(4-{4-amino-2-(1-butyl- 6-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 520 14B I-11B

(S)-3-(4-{4-amino-2-(1-butyl- 1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 486 15B I-11B

(S)-3-(4-{4-amino-5-methyl- 6-oxo-2-[1-(4,4,4- trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 540 16B I-13B

3-(4-{4-amino-5-methyl-6- oxo-2-[1-(4,4,4- trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)- 2,2-dimethylpropanoic acid 568 17AB I- 38AB

3-(4-{4-amino-5-methyl-6- oxo-2-[1-(4,4,4- trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2- methylpropanoic acid 554 18B I-11B

(S)-3-(4-{4-amino-2-[5- fluoro-1-(4,4,4- trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin- 5-yl}phenyl)propanoic acid 558 19B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(4,4,4- trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin- 5-yl}phenyl)propanoic acid 574 20B I-11B

(S)-3-(4-{4-amino-5-methyl- 2-[6-methyl-1-(4,4,4- trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 554 21B I-11B

(S)-3-(4-{4-amino-2-[1-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin- 5-yl}phenyl)propanoic acid 538 22A I-15A

3-(3-{4-amino-2-[1-(2- fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid 538 23B I-11B

(S)-3-(4-{4-amino-2-[5- fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanoic acid 556 24AI-15A

3-(3-{4-amino-2-[5-fluoro-1- (2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]- 5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin- 5-yl}phenyl)propanoic acid 556 25B I-11B

(S)-3-(4-{4-amino-2-[1-(2,3- difluoro-4-methylbenzyl)-6-methyl-1H-pyrazolo[3,4- b]pyridin-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 584 26B I-37B

3-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}benzoic acid 581 27B I-39B

3-(3-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)-2,2- dimethylpropanoic acid 63828B I-25B

(4-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}-1H-1,2,3-triazol-1- yl)acetic acid 58629B I-24B

3-(4-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}-1H-1,2,3-triazol-1- yl)propanoic acid 60030B I-26B

2-(4-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}-1H-1,2,3-triazol-1-yl)-2- methylpropanoicacid 614 31B I-27B

3-(4-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropanoic acid 628 32B I-28B

1-[(4-{4-amino-2-[6-chloro- 1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1- yl)methyl] cyclopropanecarboxylic acid 626 33BI-13B

3-(4-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)-2,2- dimethylpropanoic acid 63734AA I- 38AA

3-(4-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)-2- methylpropanoic acid 623 34ABI- 38AB

3-(4-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)-2- methylpropanoic acid 623 35BI-25B

2-{4-[4-amino-2-(1-butyl-6- chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1H-1,2,3-triazol-1- yl}acetic acid 496 36B I-24B

3-{4-[4-amino-2-(1-butyl-6- chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1H-1,2,3-triazol-1- yl}propanoic acid 510 37B I-13B

3-{4-[4-amino-2-(1-butyl-6- chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin- 5-yl]phenyl}-2,2-dimethylpropanoic acid 547 38B I-11B

(S)-3-{4-[4-amino-2-(1-butyl- 6-chloro-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic acid 519 39B I-39B

3-(3-{4-amino-2-[6-chloro-1- (2-methoxyethyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2- dimethylpropanoic acid 549 40B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(2-methoxyethyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 521 41B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(4,4,4- trifluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 573 42B I-13B

3-(4-{4-amino-2-[6-chloro-1- (4,4,4-trifluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-2,2- dimethylpropanoic acid 601 43B I-11B

(S)-3-{4-[4-amino-2-(6- chloro-1-pentyl-1H-indazol-3-yl)-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl]phenyl}propanoic acid 533 44B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(cyclohexylmethyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 559 45B I-11B

(S)-3-{4-[4-amino-2-(6- chloro-1-hexyl-1H-indazol-3-yl)-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl]phenyl}propanoic acid 547 46B I-11B

(S)-3-(4-{4-amino-2-[6- fluoro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid 593 47B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 571 48A I-15A

3-(3-{4-amino-2-(6-chloro-1- (2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 571 49A I-36A

4-(2-{4-amino-2-(6-chloro-1- (2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4- yl)butanoic acid 592 50A I-33A

3-(2-{4-amino-2-(6-chloro-1- (2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4- yl)propanoic acid 562 51B I-34B

2-(2-{4-amino-2-(6-chloro-1- (2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4- yl)acetic acid 548 52B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(4,4- dimethylpentyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 561 53A I-15A

3-(3-{4-amino-2-[1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 537 54A I-33A

3-(2-{4-amino-2-[1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4- yl)propanoic acid 528 55A I-36A

4-(2-{4-amino-2-[1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4- yl)butanoic acid 558 56A I-42A

3-(2-{4-amino-2-[1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4- yl)-2,2-dimethylpropanoic acid 556 57B I-11B

(S)-3-(4-[4-amino-2-{6- chloro-1-[(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}- 5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin- 5-yl]phenyl)propanoic acid 572 58B I-11B

(S)-3-(4-[4-amino-2-{6- chloro-1-[(4,4- difluorocyclohexyl)methyl]-1H-indazol-3-yl}-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl]phenyl)propanoic acid 595 59B I-11B

(S)-3-(4-{4-amino-2-[1-(2- fluorobenzyl)-6-methyl-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid 551 60B I-11B

(S)-3-(4-{4-amino-2-[6- fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 555 61A I-15A

3-(3-{4-amino-2-[6-fluoro-1- (2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 555 62A I-35A

(S)-3-(2-{4-amino-2-[6- fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}-1,3-thiazol-4-yl)-2,2- dimethylpropanoicacid 590 63A I-42A

3-(2-{4-amino-2-[6-fluoro-1- (2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4- yl)-2,2-dimethylpropanoic acid 574 64B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(2,6- difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 589 65B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(4-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 571 66B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 567 67B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(4-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 567 68B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(2-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 567 69B I-11B

(S)-3-(4-{4-amino-2-[6- chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 571 70B I-11B

(S)-3-(4-{2-[1-(adamantan-1- ylmethyl)-6-chloro-1H-indazol-3-yl]-4-amino-5- methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin- 5-yl}phenyl)propanoic acid 611 71B I-11B

(S)-3-(4-{4-amino-2-[5- fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 555 72A I-42A

3-(2-{4-amino-2-[5-fluoro-1- (2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4- yl)-2,2-dimethylpropanoic acid 574 73B I-11B

(S)-3-(4-{4-amino-2-[5- chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}phenyl)propanoic acid 571 74A I-42A

3-(2-{4-amino-2-[5-chloro-1- (2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}oxazol-4- yl)-2,2-dimethylpropanoic acid 590 75A I-43A

(S)-3-(2-{4-amino-2-[1-(2,3- difluoro-4-methylbenzyl)-6-methyl-1H-pyrazolo[3,4- b]pyridin-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5- yl}thiazol-4-yl)-2,2- dimethylpropanoic acid619

Example 76B(S)-3-(4-{4-Amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoicacid

Step A—(S)-methyl3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoate

The title compound was prepared using essentially the same proceduresdescribed in Example 11 Step A, using intermediate I-A15 and I-11B asstarting material.

Step B—(S)-methyl3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoate

A flask under nitrogen, containing (S)-methyl3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoate(100 mg, 0.17 mmol) and palladium on carbon (50 mg, 10 wt %) in MeOH (8mL) was purged with hydrogen. The mixture was stirred at RT for 6 hunder an atmosphere of hydrogen (˜2 atm). The solid was filtered out andwashed with MeOH (3×). The filtrate was concentrated in vacuo todryness. The residue was purified by silica gel column chromatographywith MeOH:DCM (0-10%) to afford the title compound. m/z=551 (M+1).

StepC—(S)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoicacid

To a flask containing (S)-methyl3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoate(80 mg, 0.145 mmol) in MeOH (5 mL) was added LiOH (35 mg, 1.45 mmol) in1 mL of water. The resulting mixture was stirred for 16 h at RT beforebeen concentrated in vacuo. The residue was diluted with hydrochloricacid (14.5 mL, 0.1 N), the solid was collected by filtration, washedwith water and dried in vacuo. The residue was then purified by reversephase HPLC (ACN/water with 0.05% TFA modifier) to afford the titlecompound Ex-76B. ¹H NMR (400 MHz, CD₃OD) δ 8.63 (d, J=8.0 Hz, 1H), 7.76(d, J=8.8 Hz, 1H), 7.57 (dd, J=8.0, 7.6 Hz, 1H), 7.45-7.28 (m, 6H),7.22-7.11 (m, 3H), 5.92 (s, 2H), 2.93 (t, J=7.2 Hz, 2H), 2.61 (t, J=7.2Hz, 2H), 1.95 (s, 3H); m/z=537 (M+1).

Example 77B(S)-3-(2-{4-Amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoicacid

Step A—(S)-ethyl4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

To a mixture of I-A2 (1.0 g, 3.2 mmol) and I-40B (1.16 g, 4.88 mmol) inTHF (65 mL) at RT was added triethylamine (1.3 mL, 9.76 mmol). Theresulting mixture was warmed at 65° C. for 16 h. The reaction was cooledto RT and concentrated in vacuo to dryness. The residue was purified bysilica gel chromatography using MeOH:DCM (1-10%) to afford the titlecompound. m/z=500 (M+1).

StepB—(S)-4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide

In a sealed tube containing (S)-ethyl4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate(1.5 g, 3.00 mmol) was added ammonia (30 mL, 3 N in MeOH). The resultingmixture was warmed at 40° C. for 16 h. The reaction was cooled to RT andconcentrated in vacuo to dryness. The residue was purified by silica gelchromatography using MeOH:DCM (5%) to afford the title compound. m/z=471(M+1).

StepC—(S)-4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carbothioamide

Into a flask was placed(S)-4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide(1.1 g, 2.34 mmol) Lawesson's Reagent (1.1 g, 2.81 mmol) and toluene (67mL). The resulting mixture was warmed at 80° C. for 16 h. The reactionwas quenched by the addition of aq. sat. NaHCO₃, extracted with EtOAc(3×). The organic layer was washed with brine, dried over anhydr.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography with MeOH:DCM(5%) to afford the title compound. m/z=487 (M+1).

Step D—(S)-ethyl3-(2-(4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)thiazol-4-yl)-2,2-dimethylpropanoate

In a sealed tube containing(S)-4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carbothioamide(60 mg, 0.123 mmol) and ethyl 5-bromo-2,2-dimethyl-4-oxopentanoate (48.9mg, 0.185 mmol) in EtOH (1.2 mL) was warmed at 80° C. for 16 h. Thereaction was cooled to RT and concentrated in vacuo to dryness. Theresidue was purified by silica gel chromatography using (EtOAc:EtOH3:1): Hexane to afford the title compound. m/z=639 (M+1).

StepE—(S)-3-(2-{4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoicacid

Into a flask was placed (S)-ethyl3-(2-(4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)thiazol-4-yl)-2,2-dimethylpropanoate(130 mg, 0.12 mmol), LiOH (29 mg, 1.22 mmol) dioxane (2.2 mL) and water(2.2 mL) The resulting mixture was stirred at 60° C. for 16 h. Thereaction was cooled to RT, conc. in vacuo then diluted in EtOAc andwater, and acetic acid (84 μl, 1.46 mmol) was added. The resultingsolution was extracted with EtOAc. The organic layer was washed withbrine, dried over anhydr. MgSO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with (EtOAc:EtOH 3:1): hexane to afford the titlecompound Ex-77B. ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 11.45 (s,1H), 9.02 (dd, J=8.1, 1.7 Hz, 1H), 8.63 (dd, J=4.5, 1.6 Hz, 1H), 7.37(dd, J=8.1, 4.5 Hz, 1H), 7.24 (s, 1H), 6.96 (s, 2H), 4.87 (t, J=6.8 Hz,2H), 3.06-2.85 (m, 4H), 1.80 (s, 3H), 1.08 (s, 6H); m/z=611 (M+1).

Example 78A(2-{4-Amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)aceticacid

(2-{4-Amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)aceticacid was prepared using essentially the same procedures described inExample 77, using racemic I-30 as starting material to form racemicethyl4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate.

Step A—ethyl4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

Into a flask was placed I-A2 (1.0 g, 3.2 mmol), I-30 (0.85 g, 3.6 mmol),potassium bicarbonate (390 mg, 3.9 mmol) and t-BuOH (100 mL). Theresulting mixture was warmed at 70° C. for 8 h. reaction was cooled toRT and quenched by the addition of water. The resulting solution wasextracted with EtOAc (3×) and the organic layers were combined, driedover anhydr. Na₂SO₄, filtered and the filtrate was concentrated in vacuoto dryness. The residue was purified by silica gel chromatography usingMeOH:DCM (I-10%) to afford the title compound.

Racemic methyl2-(2-{4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)acetatewas prepared as described in Ex-77B Step B and C using ethyl4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylateas starting material.

Step D. Racemic methyl2-(2-{4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)acetatewas resolved using Chiral SFC (CHIRALPAK® AD-H) to afford isomers A(faster eluting) and B (slower eluting). Isomer A was then hydrolysedusing previously described conditions (step E in Ex-77B) to affordEx-78A. ¹H NMR (300 MHz, DMSO-d₆) δ 10.45 (br s, 1H), 11.43 (s, 1H),9.04 (dd, J=8.1, 1.5 Hz, 1H), 8.64 (dd, J=4.5, 1.5 Hz, 1H), 7.45 (s,1H), 7.38 (dd, J=8.1, 4.5 Hz, 1H), 6.94 (br s, 2H), 4.88 (t, J=6.6 Hz,2H), 3.73 (s, 1H), 3.4-2.91 (m, 2H); 1.84 (s, 3H); m/z=569 (M+1).

Using essentially the same procedures to those described in examples 77Band 78A, the following compounds in Table 10 were prepared. Thechirality of the compounds in Table 15 results from the use of a chiralintermediate and/or the separation of isomers performed at Step D or E.

TABLE 15 Int. SM/ Chiral Reso- lution Step/ Step D Structure/ Ex. ColumnBromoketone m/z (M + 1) Name 79B I-40B/ Chiral Int.

(S)-3-(2-{4-amino-5- methyl-6-oxo-2-[1- (3,3,4,4,4-pentafluorobutyl)-1H- pyrazolo[3,4-b]pyridin- 3-yl]-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-3- methylbutanoic acid80BA I-40B/ Step D/ AD

(5S)-2-(2-{-4-amino-5- methyl-6-oxo-2-[1- (3,3,4,4,4-pentafluorobutyl)-1H- pyrazolo[3,4-b]pyridin- 3-yl]-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- thiazol-4- yl)cyclopropane-carboxylic acid 81B I-40B/ Chiral Int.

(S)-1-[(2-{4-amino-5- methyl-6-oxo-2-[1- (3,3,4,4,4-pentafluorobutyl)-1H- pyrazolo[3,4-b]pyridin- 3-yl]-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- thiazol-4- yl)methyl]cyclopropane-carboxylic acid 82B I-40B/ Chiral Int.

(S)-3-(2-{4-amino-5- methyl-6-oxo-2-[1- (3,3,4,4,4-pentafluorobutyl)-1H- pyrazolo[3,4-b]pyridin- 3-yl]-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- thiazol-4-yl)propanoic acid 83BI-40B/ Chiral Int.

(S)-(2-{4-amino-5- methyl-6-oxo-2-[1- (3,3,4,4,4- pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin- 3-yl]-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-4- methyl-1,3-thiazol-5- yl)acetic acid 84A I-30/ StepE/ AD

3-(2-{4-amino-2-[5- fluoro-1-(3,3,4,4,4- pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin- 3-yl]-5-methyl-6-oxo- 6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2- dimethylpropanoicacid 85A I-30/ Step D/ IA

3-(2-{4-amino-2-[5- fluoro-1-(3,3,3- trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin- 3-yl]-5-methyl-6-oxo- 6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2- dimethylpropanoicacid 86A I-30/ Step D/ IA

3-{2-[4-amino-2-(1- butyl-1H-pyrazolo[3,4- b]pyridin-3-yl)-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl]-1,3-thiazol-4-yl}-2,2- dimethylpropanoic acid 87B I-40B/ Chiral Int.

(S)-3-(2-{4-amino-5- methyl-6-oxo-2-[1- (4,4,4-trifluorobutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl]-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2- dimethylpropanoic acid 88BI-40B/ Chiral Int.

(S)-3-(2-{4-amino-5- methyl-6-oxo-2-[1- (4,4,4-trifluorobutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl]-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3- thiazol-4-yl)propanoic acid 89B I-40B/ ChiralInt.

(S)-3-(2-{4-amino-2-[6- chloro-1-(4,4,4- trifluorobutyl)-1H-pyrazolo[3,4-b]pyridin- 3-yl]-5-methyl-6-oxo- 6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2- dimethylpropanoicacid 90B I-40B/ Chiral Int.

(S)-3-(2-{4-amino-2-[1- (2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2- dimethylpropanoic acid 91BI-40B/ Chiral Int.

(S)-3-(2-{4-amino-2-[5- fluoro-1-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin- 3-yl]-5-methyl-6-oxo- 6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2- dimethylpropanoicacid 92B I-40B/ Chiral Int.

(S)-3-(2-{4-amino-2-[6- chloro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5-methyl- 6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2- dimethylpropanoic acid 93AI-30/ Step D/ IA

3-(2-{4-amino-2-[6- chloro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5-methyl- 6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3- thiazol-4-yl)benzoic acid 94B I-30/ Step D/ AS

4-(2-{4-amino-2-[6- chloro-1-(3,3,4,4,4- pentafluorobutyl)-1H-indazol-3-yl]-5-methyl- 6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-5- methyl-1,3-thiazol-4- yl)benzoic acid 95B I-40B/Chiral Int.

(S)-3-(2-{4-amino-2-[6- chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl- 6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2- dimethylpropanoic acid 96B1-41B/ Chiral Int.

3-(2-{4-amino-5- cyclopropyl-2-[5-fluoro- 1-(4,4,4-trifluorobutyl)-1H-pyrazolo[3,4- b]pyridin-3-yl]-6-oxo- 6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl}thiazol-4-yl)-2,2- dimethylpropanoic acid

Example 97B(S)-3-(2-{4-Amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-N-hydroxy-2,2-dimethylpropanamide

A flask containing example 77B (80 mg, 0.13 mmol), triethylamine (53 mg,0.52 mmol),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (100 mg, 0.26 mmol) in DMF (5 mL) was stirredfor 10 min at RT before hydroxylammonium chloride (18 mg, 0.26 mmol) wasadded. The resulting mixture was stirred for 1 h at RT then wasconcentrated in vacuo to dryness. The residue was purified by silica gelcolumn chromatography with MeOH:DCM (2-4%) then by reverse phase HPLC(ACN/water with 0.05% NH₄HCO₃ modifier) to afford the title compoundEx-97B. ¹H NMR (300 MHz, CD₃OD) δ 9.00 (dd, J=1.5, 8.1 Hz, 1H), 8.58(dd, J=1.5, 4.5 Hz, 1H), 7.32 (dd, J=4.5, 8.1 Hz, 1H), 7.12 (s, 1H),4.91 (t, J=7.2 Hz, 2H), 3.11-2.82 (m, 4H), 1.83 (s, 3H), 1.18 (s, 3H),1.14 (s, 3H); m/z 626 (M+1).

Example 98A[5-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-oxo-1,3,4-oxadiazol-3(2H)-yl]aceticacid

Step A

ethyl4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylatewas prepared using conditions similar to the those described for thesynthesis of ethyl4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate,using I-A1 and I-30 as starting material.

StepB—4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carbohydrazide

A flask containing ethyl4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate(900 mg, 1.69 mmol) and hydrazine hydrate (863 mg, 16.89 mmol) in MeOH(10 mL) was stirred for 2 h at 70° C. The solid was collected byfiltration to afford the title compound which was used in Step C withoutpurification.

StepC—5-(4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one

A flask containing4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carbohydrazide(400 mg, 0.77 mmol) and N,N-carbonyldiimidazole (375 mg, 2.31 mmol) inDCM (25 mL) was stirred for 2 h at RT. The resulting mixture wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with MeOH:DCM (2-4%) to afford the title compound.

Step D—ethyl2-(5-(4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-oxo-1,3,4-oxadiazol-3(2H)-yl)acetate

To a flask containing5-(4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,3,4-oxadiazol-2(3H)-one(150 mg, 0.28 mmol), and potassium carbonate (19 mg, 0.14 mmol) in DMF(20 mL) at −20° C. was added ethyl 2-bromoacetate (41.5 mg, 0.25 mmol)and the mixture was stirred for 5 h at −20° C. The reaction wasconcentrated in vacuo to dryness. The residue was purified by silica gelchromatography using MeOH:DCM (2-10%) to afford the title racemicproduct. The racemic material was resolved using chiral SFC (CHIRALCEL®OD-H column) to afford isomer A (faster eluting) and isomer B (slowereluting).

StepE—[5-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-oxo-1,3,4-oxadiazol-3(2H)-yl]aceticacid

To a flask containing ethyl2-(5-(4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-oxo-1,3,4-oxadiazol-3(2H)-yl)acetateisomer A (25 mg, 0.04 mmol), in THF (3 mL) was added LiOH (2.9 mg, 0.12mmol) in water (1 mL). The resulting mixture was stirred for 2 h at RTbefore being concentrated in vacuo. The residue was diluted withhydrochloric acid (0.1 N, 1.1 mL), the solid was collected byfiltration, washed with water and dried under vacuum to afford the titleproduct Ex-98A. ¹H NMR (300 MHz, CD₃OD) δ 8.64 (d, J=8.4 Hz, 1H), 7.72(d, J=1.2 Hz, 1H), 7.24 (dd, J=1.8, 8.7 Hz, 1H), 4.80-4.74 (m, 2H), 4.27(s, 2H), 3.06-2.83 (m, 2H), 1.82 (s, 3H); m/z 603 (M+1).

Example 99B2-[5-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-oxo-1,3,4-oxadiazol-3(2H)-yl]-2-methylpropanoicacid

The title compound was prepared using essentially the same proceduresdescribed in Example 98A, using methyl 2-bromo-2-methylpropanoate asstarting material. The racemic Ex-99 was resolved using chiral SFC(Kromasil (R,R) WHELK-01 5/100 column) to afford isomers Ex-99A (fastereluting) and Ex-99B (slower eluting) of the title compound ¹H NMR (300MHz, CD₃OD) δ 8.68 (d, J=8.7 Hz, 1H), 7.78 (d, J=1.5 Hz, 1H), 7.29 (dd,J=1.5, 8.7 Hz, 1H), 4.95-4.80 (m, 2H), 3.11-2.86 (m, 2H), 1.86 (s, 3H),1.75 (s, 3H), 1.74 (s, 3H); m/z 631 (M+1).

Example 100B(S)-(3-(4-{4-Amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)glycine

Step A—(S)-tert-butyl(3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoyl)glycinate

In a flask containing Ex-21B (20 mg, 0.037 mmol) andO-(benzotriazol-1-yl)-N,N,N′,N-tetramethyluronium tetrafluoroborate(12.19 mg, 0.04 mmol) in DMF (300 μl) at RT was added triethylamine (52μl, 0.37 mmol). Then glycine tert-butyl ester hydrochloride (18 mg,0.112 mmol) was added. The resulting mixture was stirred 20 min at RT.Volatiles were removed in vacuo, and then water was added and the solidwas collected and dried under vacuum. The crude material was useddirectly in the next step.

StepB—(S)-(3-(4-(4-amino-2-(1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)propanoyl)glycine

To the crude product from step A was added trifluoroacetic acid (250 μl,3.24 mmol) and DCM (0.7 mL) and the reaction was stirred for 2 h at RT.The reaction mixture was then concentrated in vacuo to dryness. Themixture was filtered and purified by mass triggered reverse phase HPLC(ACN/water with 0.1% TFA modifier) to afford the title compound Ex-100Bas the TFA salt. ¹H NMR (500 MHz, DMSO-d₆) δ 9.06 (dd, J=8.0, 1.7 Hz,1H), 8.65 (dd, J=4.5, 1.7 Hz, 1H), 8.15 (d, J=5.9 Hz, 1H), 7.43-7.31 (m,2H), 7.23-7.10 (m, 7H), 6.55 (s, 2H), 5.83 (s, 2H), 3.71 (d, J=5.8 Hz,2H), 2.79 (t, J=7.9 Hz, 2H), 2.41 (t, J=8.0 Hz, 2H), 1.77 (s, 3H);m/z=595.3 (M+1).

Using a similar procedure to that described in Ex-100B, the followingcompounds in Table 16 were prepared using from commercial startingreagents or compounds known in the literature. Methyl esters werehydrolysed using lithium hydroxide conditions previously described.

TABLE 16 Step A m/z Ex. amine Structure Name (M + 1) 101B

(S)-2-(3-(4-{4-amino-2- [1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanamido)-2-methylpropanoic acid 623 102B

(5S)-(3-(4-{4-amino-2-[1- (2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoyl)-D- alanine 609 103B

(5S)-(3-(4-{4-amino-2-[1- (2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoyl)-L- alanine 609 104B

(5S,2R)-2-(3-(4-{4- amino-2-[1-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanamido) butanoicacid 623 105B

(5S,2S)-2-(3-(4-{4- amino-2-[1-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3- yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5- yl}phenyl)propanamido) butanoicacid 623 106B

(5S)-(3-(4-{4-amino-2-[1- (2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoyl)-D- serine 625 107B

(5S)-(3-(4-{4-amino-2-[1- (2-fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoyl)-D- threonine 639

Example 108B(S)—N-((2H-Tetrazol-5-yl)methyl)-3-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamide

In a flask containing Ex-21B (20 mg, 0.037 mmol) andO-(benzotriazol-1-yl)-N,N,N′NV-tetramethyluronium tetrafluoroborate(29.9 mg, 0.093 mmol) in DMF (300 μl) at RT was added triethylamine (26μl, 0.186 mmol). Then (2-trityl-2H-tetrazol-5-yl)methanamine (40 mg,0.11 mmol) was added. The resulting mixture was stirred 20 min at RT.The reaction was concentrated in vacuo to dryness then water was addedand the solid was collected and dried under vacuum. The residue wastreated with HCl (1 mL, 4 M in dioxane) and the resulting mixture wasstirred at 80° C. then concentrated in vacuo to dryness and the residuewas purified by mass triggered reverse phase HPLC (ACN/water with 0.1%TFA modifier) to afford the title compound Ex-108B as the TFA salt. ¹HNMR (500 MHz, DMSO-d₆) δ 11.10 (s, 1H), 9.06 (dd, J=8.1, 1.6 Hz, 1H),8.65 (dd, J=4.5, 1.6 Hz, 1H), 8.58 (t, J=5.7 Hz, 1H), 7.43-7.32 (m, 2H),7.29-7.11 (m, 7H), 6.55 (s, 2H), 5.84 (s, 2H), 4.53 (d, J=5.6 Hz, 2H),2.81 (t, J=8.0 Hz, 2H), 2.44 (t, J=8.0 Hz, 2H), 1.78 (s, 3H); m/z=619(M+1).

Example 109B3-(4-{4-Amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2H-1,2,3-triazol-2-yl)propanoicacid

StepA—4-amino-5-ethynyl-5-methyl-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

To a flask containing I-A2 (400 mg, 1.30 mmol) and I-10B (272 mg, 1.43mmol) in t-BuOH (10 mL) was added potassium bicarbonate (130 mg, 1.30mmol). The resulting mixture was stirred at 70° C. for 16 h thenquenched by the addition of brine and extracted with EtOAc (3×). Thecombined organic layer was washed with brine, dried over anhydr. Na₂SO₄,and filtered. The filtrate was concentrated in vacuo, the residue waspurified by silica gel column chromatography with MeOH:DCM to afford thetitle compound.

StepB—4-amino-5-methyl-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(1H-1,2,3-triazol-4-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

To a microwave vial containing4-amino-5-ethynyl-5-methyl-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one(500 mg, 1.11 mmol) and bromotris(triphenylphosphine)copper (I) (103 mg,0.11 mmol) in DMSO (22 mL) was added azidotrimethylsilane (770 μL, 5.54mmol). The reaction mixture was microwaved at 120° C. for 1 h. Theresulting mixture was cooled to RT and diluted with EtOAc and brine. Tothe organic phase was added aq. ammonium hydroxide solution and theresulting mixture was stirred 16 h. The aqueous was extracted with EtOAc(3×) dried over anhydr. MgSO₄, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with (EtOAc:EtOH 3:1): hexane gradient to afford thetitle compound.

Step C—Ethyl3-(4-(4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)-2H-1,2,3-triazol-2-yl)propanoate

To a flask containing4-amino-5-methyl-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-(1H-1,2,3-triazol-4-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one(160 mg, 0.29 mmol) and K₂CO₃ (121 mg, 0.87 mmol) in DMF (2.9 mL) wasadded ethyl acrylate (38 μl, 0.35 mmol) The resulting mixture wasstirred 2 h at RT then diluted with EtOAc and brine. The organic layerwas washed with brine, dried over anhydr. MgSO₄, and filtered. Thefiltrate was concentrated in vacuo and the residue was first purified bysilica gel column chromatography with (EtOAc:EtOH 3:1):hexane then bymass triggered reverse phase HPLC (ACN/water with 0.1% TFA modifier) toafford the title compound as the TFA salt.

StepD—3-(4-{4-amino-5-methyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2H-1,2,3-triazol-2-yl)propanoicacid

To a flask containing ethyl3-(4-(4-amino-5-methyl-6-oxo-2-(1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)-2H-1,2,3-triazol-2-yl)propanoate(22 mg, 0.037 mmol) in MeCN (1.8 mL) and water (1.8 mL) was added LiOH(5 mg, 0.18 mmol). The resulting mixture was stirred 30 min at RT thendiluted in EtOAc and acetic acid (13 μl, 0.22 mmol). The resultingsolution was extracted with EtOAc. The organic layer was washed withbrine, dried over anhydr. MgSO₄, and filtered. The filtrate wasconcentrated in vacuo and purified by silica gel column chromatographywith (EtOAc:EtOH 3:1): Hexane to afford the title compound Ex-109B. ¹HNMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H), 9.02 (dd, J=8.1, 1.7 Hz, 1H),8.63 (dd, J=4.5, 1.6 Hz, 1H), 7.73 (s, 1H), 7.37 (dd, J=8.1, 4.5 Hz,1H), 6.62 (s, 2H), 4.87 (t, J=6.7 Hz, 2H), 4.49 (t, J=7.2 Hz, 2H), 2.94(dt, J=19.1, 6.8 Hz, 3H), 2.71 (t, J=7.1 Hz, 2H), 1.75 (s, 3H).m/z=567.1 (M+1).

Example 110B(S)-3-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-5-hydroxy-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoicacid

Step A—(S)-methyl3-(4-(4-amino-2-(6-chloro-1-(2-fluorobenzyl)-5-methoxy-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)propanoate

A flask containing I-A24 (100 mg, 0.30 mmol), I-11B (99 mg, 0.30 mmol)and potassium bicarbonate (90 mg, 0.90 mmol) in t-BuOH (10 mL) wasstirred for 16 h at 70° C. The reaction mixture was concentrated invacuo to dryness. The residue was purified by silica gel columnchromatography with MeOH:DCM (0-5%) to afford the title compound.

StepB—(S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-5-hydroxy-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoicacid

To a flask containing (S)-methyl3-(4-(4-amino-2-(6-chloro-1-(2-fluorobenzyl)-5-methoxy-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)propanoate(105 mg, 0.17 mmol) in DCM (10 mL) at 0° C. was added dropwisetribromoborane (1.0 mL, 10.6 mmol). The resulting mixture was stirredfor 16 h at RT. The reaction was quenched by the addition of ice waterand the pH value of the mixture was adjusted to pH 7-8 by the additionof NaHCO₃. The resulting solution was extracted with EtOAc (3×), theorganic layer was washed with brine, dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography with MeOH:DCM (1-6%) toafford the title compound Ex-110B, ¹H NMR (300 MHz, CD₃OD): δ 8.10 (s,1H), 7.59 (s, 1H), 7.30-7.20 (m, 5H), 7.15-7.06 (m, 3H), 5.70 (s, 2H),2.87 (t, J=7.2 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.84 (s, 3H); m/z 587(M+1).

Example 111B(S)-3-{4-[4-amino-2-(1-butyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoicacid

Step A—(S)-methyl3-(4-(4-amino-2-(1-butyl-6-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)propanoate

A flask containing I-A36 (50 mg, 0.20 mmol), I-11B (65 mg, 0.20 mmol)and potassium bicarbonate (60 mg, 0.60 mmol) in t-BuOH (5 mL) wasstirred for 16 h at 75° C. The reaction was cooled to RT and quenched bythe addition of water. The resulting solution was extracted with DCM(3×), the organic layers were combined, dried over anhydr. Na₂SO₄,filtered and the filtrate was concentrated in vacuo to dryness. Theresidue was purified by silica gel chromatography using MeOH:DCM (0-3%)to afford the title product.

Step B—(S)-methyl3-(4-(4-amino-2-(1-butyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)propanoate

In a flask under inert atmosphere of nitrogen were placed (S)-methyl3-(4-(4-amino-2-(1-butyl-6-chloro-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)propanoate(140 mg, 0.26 mmol), bis(triphenylphosphine)palladium(II) chloride (28mg, 0.039 mmol) and THF (10 mL). The resulting mixture was stirred for30 min before dimethylzinc (1.57 mL, 1.57 mmol, 1 M in THF) was added.The mixture was stirred for 16 h at RT. The reaction was quenched by theaddition of aq. sat. NH₄Cl, extracted with EtOAc (3×). The organic layerwas washed with brine, dried over anhydr. Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo and the residue was first purified bysilica gel column chromatography with MeOH:DCM (0-10%) then by reversephase HPLC (ACN/water with 0.05% NH₄HCO₃ modifier) to afford the titlecompound.

StepC—(S)-3-{4-[4-amino-2-(1-butyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoicacid

To a flask containing (S)-methyl3-(4-(4-amino-2-(1-butyl-6-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)propanoate(70 mg, 0.14 mmol) in THF (8 mL) was added LiOH (16 mg, 0.68 mmol) inwater (0.5 mL). The resulting mixture was stirred for 16 h at RT beforebeen concentrated in vacuo. The residue was diluted with water (2 mL)and hydrochloric acid (6.8 mL, 0.1 N) was added. The solid was collectedby filtration and dried under vacuum to afford the title productEx-111B. ¹H NMR (400 MHz, CD₃OD) δ 8.88 (d, J=8.0 Hz, 1H), 7.30-7.20 (m,5H), 4.59 (t, J=6.8 Hz, 2H), 2.90 (t, J=7.6 Hz, 2H), 2.69 (s, 3H), 2.58(t, J=7.6 Hz, 2H), 2.02-1.95 (m, 2H), 1.87 (s, 3H), 1.40-1.34 (m, 2H),0.97 (t, J=7.6 Hz, 3H); m/z 500 (M+1).

Example 112B(S)-4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(2H-tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

StepA—(S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methynl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamide

To a flask containing Ex-47B (1.0 g, 1.58 mmol) in DMF (10 mL) was addedN,N-carbonyldiimidazole (1.28 g, 7.88 mmol). The mixture was stirred for30 min at RT and NH₄Cl (0.17 g, 3.15 mmol) was added. The resultingmixture was stirred for 16 h at RT then poured into water and extractedwith EtOAc (3×). the organic layers were combined, dried over anhydr.Na₂SO₄, filtered and the filtrate was concentrated in vacuo to dryness.The residue was purified by silica gel chromatography using MeOH:DCM(0-5%) to afford the title compound.

StepB—(S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanenitrile

To a flask containing(S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamide(800 mg, 1.40 mmol) and pyridine (0.5 mL, 6.18 mmol) in DCM (5 mL) at 0°C. was added dropwise 2,2,2-trifluoroacetic anhydride (0.5 mL, 3.54mmol). The mixture was stirred for 1 h at RT. The reaction was thendiluted with MeOH (20 mL) and concentrated in vacuo. The residue wasdiluted with water, extracted with EtOAc (3×) and the organic layerswere combined, dried over anhydr. Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo to dryness. The residue was purified by silica gelchromatography using MeOH:DCM (0-5%) to afford the title product.

StepC—(S)-4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(2H-tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

To a flask containing(S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanenitrile(170 mg, 0.31 mmol) and dibutylstannanone (15.3 mg, 0.062 mmol) intoluene (10 mL) was added azidotrimethylsilane (177 mg, 1.54 mmol). Themixture was stirred for 16 h at 100° C. then the mixture wasconcentrated in vacuo. The residue was first purified by silica gelcolumn chromatography with MeOH:DCM (0-5%) then by reverse phase HPLC(ACN/water with 0.05% NH₄HCO₃ modifier) to afford the title compoundEx-112B. ¹H NMR (300 MHz, CD₃OD) δ 8.66 (d, J=8.7 Hz, 1H), 7.63 (s, 1H),7.35-7.05 (m, 9H), 5.76 (s, 2H), 3.16-2.96 (m, 4H), 1.83 (s, 3H); m/z595 (M+1).

Example 113A4-(4-{4-Amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoicacid

StepA—4-Amino-5-(4-bromophenyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

A flask containing I-A16 (250 mg, 0.82 mmol), I-21A (263 mg, 0.82 mmol)and potassium bicarbonate (180 mg, 1.80 mmol) in t-BuOH (10 mL) wasstirred at 70° C. for 16 h. The reaction mixture was concentrated invacuo to dryness. The residue was purified by silica gel columnchromatography with MeOH:DCM (0-10%) to afford the title compound.m/z=546 (M+1).

Step B—ethyl4-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoate

To a flask under a inert atmosphere of nitrogen, containing4-amino-5-(4-bromophenyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one(150 mg, 0.28 mmol) and second generation Xphos precatalyst (43 mg,0.055 mmol) in THF (0.5 mL) was added 4-ethoxy-4-oxobutylzinc bromide(3.3 mL, 1.65 mmol). The resulting mixture was stirred at 55° C. for 16h. The reaction was quenched by the addition of aq. sat. NH₄Cl,extracted with EtOAc (3×). The organic layers were combined, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography withMeOH:DCM (0-10%) to afford the title compound.

StepC—4-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoicacid

To a flask containing ethyl4-(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoate(100 mg, 0.17 mmol) in THF (4 mL) was added LiOH (72 mg, 1.72 mmol) inwater (4 mL). The resulting mixture was stirred for 16 h at RT beforebeen concentrated in vacuo. The residue was diluted with hydrochloricacid (0.1 N, 17.2 mL), the solid was collected by filtration, washedwith water and dried under vacuum to afford the title product Ex-113A.¹H NMR (300 MHz, CD₃OD): δ 9.10 (d, J=8.1 Hz, 1H), 8.61 (dd, J=4.5 Hz,1.2 Hz, 1H), 7.40-7.06 (m, 9H), 5.92 (s, 2H), 2.65 (t, J=7.2 Hz, 2H),2.28 (t, J=7.2 Hz, 2H), 1.98-1.85 (m, 5H); m/z 552 (M+1).

Example 114A(4-{4-Amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)aceticacid

Step A—tert-butyl2-(4-(4-amino-2-{1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)acetate

In a microwave vial were placed4-amino-5-(4-bromophenyl)-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one(Ex-113A, step A, isomer A) (150 mg, 0.28 mmol),bis(dibenzylideneacetone)palladium (32 mg, 0.055 mmol),tri-tert-butylphosphonium tetrafluoroborate (32 mg, 0.11 mmol) and(2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1.07 g, 4.13 mmol) in THF(15 mL). The reaction mixture was stirred for 1 h at RT and thenmicrowaved for 1 h at 120° C. The reaction was quenched by the additionof aq. sat. NH₄Cl, extracted with EtOAc (3×). The organic layer waswashed with brine, dried over anhydr. Na₂SO₄, filtered and the filtratewas concentrated in vacuo. The residue was purified by reverse phaseHPLC (ACN/water with 0.05% NH₄HCO₃ modifier) to afford the titlecompound.

StepB—(4-{4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)aceticacid

Into a flask were placed tert-butyl2-(4-(4-amino-2-{1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl}-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)acetate(65 mg, 0.11 mmol), DCM (5 mL) and trifluoroacetic acid (1 mL). Theresulting mixture was stirred for 16 h at RT. The reaction wasconcentrated in vacuo then diluted with water. The pH value was adjustedto pH 10 by addition of sodium hydroxide (1 N) and then, the pH valuewas adjusted to pH 6 with hydrochloric acid (1 N), the solid wascollected by filtration, washed with water and dried under vacuum toafford the title product Ex-114A. ¹H NMR (300 MHz, CD₃OD) δ 9.04 (dd,J=1.8 Hz, 8.4 Hz, 1H), 8.60 (dd, J=1.8 Hz, 4.5 Hz, 1H), 7.39-7.24 (m,6H), 7.13-7.01 (m, 3H), 5.90 (s, 2H), 3.57 (s, 2H), 1.86 (s, 3H); m/z524 (M+1).

Using essentially the same procedure described in examples 113A and114A, the following compounds in Table 17 were prepared.

TABLE 17 m/z Ex Structure Name (M + 1) 115A

4-(4-{4-amino-2-[6-chloro- 1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic acid 585 116A

4-(4-{4-amino-5-methyl-6- oxo-2-[1-(3,3,4,4,4- pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl)-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)butanoic acid 590 117A

2-(4-{4-amino-2-[6-chloro- 1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic acid 557 118A

2-(4-{4-amino-5-methyl-6- oxo-2-[1-(3,3,4,4,4- pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl]-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)acetic acid 562

Example 119B3-(6-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)propanoicacid

StepA—4-amino-5-(5-bromopyridin-2-yl)-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

A flask containing I-A1 (200 mg, 0.59 mmol), I-19 (189 mg, 0.587 mmol)and potassium bicarbonate (88 mg, 0.88 mmol) in t-BuOH (10 mL) wasstirred for 16 h at 75° C. The reaction mixture was concentrated invacuo to dryness. The residue was purified by silica gel columnchromatography with MeOH:DCM (0-10%) to afford the title compound.

StepB—methyl-3-(6-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)acrylate

In a flask under a inert atmosphere of nitrogen were placed4-amino-5-(5-bromopyridin-2-yl)-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one(300 mg, 0.49 mmol), palladium (II) acetate (22 mg, 0.097 mmol),tri-tert-butylphosphine (394 mg, 0.20 mmol), triethylamine (0.14 mL,0.97 mmol) and methyl acrylate (126 mg, 1.46 mmol) in DMF (8 mL). Theresulting mixture was stirred for 16 h at 100° C. The reaction wascooled to RT and quenched by the addition of water. The resultingsolution was extracted with EtOAc (3×) and the organic layers werecombined, dried over anhydr. Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo to dryness. The residue was purified by silica gelchromatography using EtOAc:petroleum ether (20%-100%) to afford thetitle product.

Step B—methyl3-(6-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)propanoate

A flask containingmethyl-3-(6-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)acrylate(300 mg, 0.48 mmol), 4-methylbenzenesulfonhydrazide (269 mg, 1.45 mmol),sodium acetate trihydrate (328 mg, 2.41 mmol) in a mixture water (1 mL)and dimethoxyethane (10 mL) was stirred for 16 h at 80° C. The reactionwas cooled to RT and quenched by the addition of water.

The resulting solution was extracted with EtOAc (3×) and the organiclayers were combined, dried over anhydr. Na₂SO₄, filtered and thefiltrate was concentrated in vacuo to dryness. The residue was purifiedby silica gel chromatography using EtOAc:petroleum ether (30%-70%) thenby reverse phase HPLC (ACN/water with 0.05% NH₄HCO₃ modifier) to affordthe racemic title compound. The racemic material was resolved usingchiral SFC (CHIRALPAK® IC column) to afford isomer A (faster eluting)and isomer B (slower eluting).

StepC—3-(6-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)propanoicacid

To a flask containing methyl3-(6-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridin-3-yl)propanoateisomer B (70 mg, 0.11 mmol) in MeOH (2 mL) was added LiOH (13 mg, 0.56mmol) in water (1 mL). The resulting mixture was stirred for 16 h at RTbefore been concentrated in vacuo. The residue was diluted withhydrochloric acid (0.1 N, 5.6 mL), the solid was collected byfiltration, washed with water and dried under vacuum to afford the titleproduct Ex-119B. ¹H NMR (300 MHz, CD₃OD) δ 8.64 (dd, J=8.7, 3.3 Hz, 1H),8.50 (d, J=2.1 Hz, 1H), 7.73 (s, 1H), 7.70 (d, J=2.4 Hz, 1H), 7.41 (d,J=8.1 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 4.79 (t, J=6.6 Hz, 2H), 3.01-2.84(m, 4H), 2.64 (t, J=7.5 Hz, 2H), 1.89 (s, 3H); m/z 610 (M+1).

Example 120B3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-cyanophenyl)propanoicacid

Step A—methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-bromophenyl)propanoate

A flask containing I-A1 (550 mg, 1.61 mmol), I-14 (657 mg, 1.61 mmol)and potassium bicarbonate (485 mg, 4.84 mmol) in t-BuOH (25 mL) wasstirred for 16 h at 70° C. The reaction was cooled to RT and quenched bythe addition of brine. The resulting solution was extracted with EtOAc(3×) and the organic layers were combined, dried over anhydr. Na₂SO₄,filtered and the filtrate was concentrated in vacuo to dryness. Theresidue was purified by silica gel chromatography using MeOH:DCM (0-2%)to afford the title racemic product. The racemic material was resolvedusing chiral SFC (Kromasil (R,R)WHELK-01 5/100 column) to afford isomerA (faster eluting) and isomer B (slower eluting). m/z=703 (M+1).

Step B—methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-cyanophenyl)propanoate

A flask under an inert atmosphere of nitrogen containing methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-bromophenyl)propanoateisomer B (120 mg, 0.17 mmol), zinc cyanide (26 mg, 0.22 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (17.7 mg, 0.017mmol), 1,1′-bis(diphenylphosphino)ferrocene (19 mg, 0.034 mmol) and zinc(11 mg, 0.17 mmol) in DMF (10 mL) was stirred for 1 h at 120° C. Thereaction was cooled to RT and quenched by the addition of brine. Theresulting solution was extracted with EtOAc (3×) and the organic layerswere combined, dried over anhydr. Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo to dryness. The residue was purified by silica gelchromatography using MeOH:DCM (0-2%) to afford the title product.

StepC—3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-cyanophenyl)propanoicacid

To a flask containing methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-cyanophenyl)propanoate(58 mg, 0.090 mmol) in THF (2 mL) was added LiOH (38 mg, 0.90 mmol) inwater (2 mL). The resulting mixture was stirred for 1 h at RT beforebeen concentrated in vacuo. The residue was diluted with hydrochloricacid (0.1 N, 8.9 mL), the solid was collected by filtration, washed withwater and dried under vacuum to afford the title product Ex-120B. ¹H NMR(300 MHz, CD₃OD) δ 8.64 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 7.68 (s, 1H),7.52-7.42 (m, 2H), 7.24 (d, J=8.7 Hz, 1H), 4.82-4.76 (m, 2H), 3.10 (t,J=7.2 Hz, 2H), 3.00-2.82 (m, 2H), 2.70-2.60 (m, 2H), 1.87 (s, 3H); m/z634 (M+1).

Example 121B3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylphenyl)propanoicacid

Step A—methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylphenyl)propanoate

To a microwave tube under an inert atmosphere of nitrogen was addedmethyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-bromophenyl)propanoateisomer B (100 mg, 0.14 mmol),1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (9.3 mg,0.014 mmol) potassium carbonate (197 mg, 1.43 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (322 mg, 1.28 mmol) anddioxane (10 mL). The tube was flushed with nitrogen for 4 min thenmicrowaved for 2 h at 70° C. The reaction was cooled to RT and quenchedby the addition of brine. The resulting solution was extracted withEtOAc (3×) and the organic layers were combined, dried over anhydr.Na₂SO₄, filtered and the filtrate was concentrated in vacuo to dryness.The residue was purified by silica gel chromatography using MeOH:DCM(0-2%) to afford the title product.

StepB—3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylphenyl)propanoicacid

To a flask containing methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylphenyl)propanoate(55 mg, 0.086 mmol) in THF (2 mL) was added LiOH (36 mg, 0.86 mmol) inwater (2 mL). The resulting mixture was stirred for 1 h at RT beforebeing concentrated in vacuo. The residue was diluted with hydrochloricacid (0.1 N, 8.6 mL), the solid was collected by filtration, washed withwater and dried under vacuum to afford the title product Ex-121B. ¹H NMR(300 MHz, CD₃OD) δ 8.64 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 7.24 (d, J=8.7Hz, 1H), 7.17-7.07 (m, 3H), 4.80-4.76 (m, 2H), 3.00-2.82 (m, 4H), 2.51(t, J=7.8 Hz, 2H), 2.29 (s, 3H), 1.87 (s, 3H); m/z 623 (M+1).

Example 122B3-(4-{4-Amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-hydroxyphenyl)propanoicacid

Step A—methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)propanoate

A flask containing I-A1 (143 mg, 0.42 mmol), I-17 (150 mg, 0.42 mmol)and potassium bicarbonate (51 mg, 0.51 mmol) in t-BuOH (5 mL) wasstirred for 16 h at 70° C. The reaction mixture was concentrated invacuo to dryness. The residue was purified by silica gel columnchromatography with MeOH:DCM (0-10%) to afford the racemic titlecompound. The racemic material was resolved using Chiral SFC (PhenomenexLux 5u Cellulose-4) to afford isomer A (faster eluting) and isomer B(slower eluting).

StepB—4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-5-(2-oxochroman-7-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

To a flask containing methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methoxyphenyl)propanoateisomer A (60 mg, 0.092 mmol) in DCM (1 mL) at 0° C. was added dropwisetribromoborane (0.2 mL, 2.11 mmol). The resulting mixture was stirred 1h at 0° C. then 16 h at RT. The reaction was then quenched by theaddition of sodium hydroxide. The pH value of the solution was adjustedto pH 6 bu the addition of hydrochloric acid (2 N). The resultingsolution was extracted with EtOAc (3×) and the organic layers werecombined, dried over anhydr. Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo to dryness to afford the title product.

Step C—methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-hydroxyphenyl)propanoate

A flask containing4-amino-2-(6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl)-5-methyl-5-(2-oxochroman-7-yl)-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one(60 mg, 0.099 mmol) in MeOH (4 mL) was stirred for 3 h at 110° C. Thereaction mixture was concentrated in vacuo to dryness to afford thetitle product.

StepD—3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-hydroxyphenyl)propanoicacid

To a flask containing methyl3-(4-{4-amino-2-[6-chloro-1-(3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-hydroxyphenyl)propanoate(60 mg, 0.094 mmol) in THF (4 mL) was added sodium hydroxide (19 mg,0.47 mmol) in water (0.5 mL). The resulting mixture was stirred for 6 hat RT then concentrated in vacuo to dryness. The residue was dilutedwith water and the pH was adjusted to pH 4 with hydrochloric acid (1 N).The resulting solution was extracted with EtOAc (3×) and the organiclayers were combined, dried over anhydr. Na₂SO₄, filtered and thefiltrate was concentrated in vacuo to dryness. The residue was dilutedwithEtOAc:DCM:hexane (1:1:4) and the solid was collected by filtrationand dried under vacuum to afford the title product Ex-122B. ¹H NMR (400MHz, CD₃OD): δ 8.70 (d, J=8.8 Hz, 1H), 7.78 (s, 1H), 7.29 (d, J=8.8 Hz,1H), 7.14 (d, J=2.4 Hz, 1H), 7.04 (dd, J=8.4 Hz, 2.4 Hz, 1H), 6.78 (d,J=8.4 Hz, 1H), 4.84 (t, J=7.2 Hz, 2H), 3.03-2.86 (m, 4H), 2.60 (t, J=7.6Hz, 2H), 1.85 (s, 3H); m/z 625 (M+1).

Examples 123A-139B

Using essentially the same procedure as described in Ex-1A, thefollowing compounds in Table 18 were prepared.

TABLE 18 Chiral Resolution m/z Ex. Int. SM Column Structure Name (M + 1)123AA I-35A Lux Cellulose-4

(5S)-3-{2-[4-amino-5- methyl-6-oxo-2-{1- [tetrahydro-2H-pyran-2-ylmethyl]-1H- pyrazolo[3,4-b]pyridin-3- yl}-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin- 5-yl]-1,3-thiazol-4-yl}- 2,2-dimethylpropanoicacid 563 123AB I-35A Lux Cellulose-4

(5S)-3-{2-[4-amino-5- methyl-6-oxo-2-{1- [tetrahydro-2H-pyran-2-ylmethyl]-1H- pyrazolo[3,4-b]pyridin-3- yl}-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin- 5-yl]-1,3-thiazol-4-yl}- 2,2-dimethylpropanoicacid 563 124AA I-42A IC

3-{2-[4-amino-5-methyl- 6-oxo-2-{1-[tetrahydro- 2H-pyran-2-ylmethyl]-1H-pyrazolo[3,4-b]pyridin-3- yl}-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}- 2,2-dimethylpropanoic acid 547 124AB I-42A IC

3-{2-[4-amino-5-methyl- 6-oxo-2-{1-[tetrahydro- 2H-pyran-2-ylmethyl]-1H-pyrazolo[3,4-b]pyridin-3- yl}-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}- 2,2-dimethylpropanoic acid 547 125AA I-35A AD-H

(5S)-3-{2-[4-amino-5- methyl-2-{1-[4- methylcyclohexylmethyl]-1H-pyrazolo[3,4- b]pyridin-3-yl}-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3- thiazol-4-yl}-2,2- dimethylpropanoic acid 575125AB I-35A AD-H

(5S)-3-{2-[4-amino-5- methyl-2-{1-[4- methylcyclohexylmethyl]-1H-pyrazolo[3,4- b]pyridin-3-yl}-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3- thiazol-4-yl}-2,2- dimethylpropanoic acid 575126AA I-42A AD

3-{2-[4-amino-5-methyl- 2-{1-[4- methylcyclohexylmethyl]-1H-pyrazolo[3,4- b]pyridin-3-yl}-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3- oxazol-4-yl}-2,2- dimethylpropanoic acid 559126AB I-42A AD

3-{2-[4-amino-5-methyl- 2-{1-[4- methylcyclohexylmethyl]-1H-pyrazolo[3,4- b]pyridin-3-yl}-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3- oxazol-4-yl}-2,2- dimethylpropanoic acid 559 127AI-54 IA

4-(2-{4-amino-2-[6- chloro-1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2- difluorobutanoic acid 612 128A I-64 IA

3-(4-{4-amino-2-[6- chloro-1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3-oxazol-2-yl)-2,2- dimethylpropanoic acid 590 129A I-62 Chiral Cellulose-SB

3-(6-{4-amino-2-[6- chloro-1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}pyridin-3-yl)propanoic acid 572 130A I-67 ID

2-{4-amino-2-[6-chloro-1- (2-fluorobenzyl)-1H- indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin- 5-yl}-1,3-benzothiazole-5-carboxylic acid 600 131B I-20 IC

3-(6-{4-amino-2-[6- chloro-1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}pyridin-3-yl)-2,2- dimethylpropanoic acid 600 132AA I-42A Chiral Cellulose- SB

3-{2-[4-amino-2-{6- chloro-1-[4- methylcyclohexylmethyl]-1H-indazol-3-yl}-5- methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3- oxazol-4-yl}-2,2- dimethylpropanoic acid 592132AB I-42A Chiral Cellulose- SB

3-{2-[4-amino-2-{6- chloro-1-[4- methylcyclohexylmethyl]-1H-indazol-3-yl}-5- methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3- oxazol-4-yl}-2,2- dimethylpropanoic acid 592133AA I-35A IC

(5S)-3-{2-[4-amino-2-{6- fluoro-1-[tetrahydro-2H- pyran-2-ylmethyl]-1H-indazol-3-yl}-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}- 2,2-dimethylpropanoic acid 580 133AB I-35A IC

(5S)-3-{2-[4-amino-2-{6- fluoro-1-[tetrahydro-2H- pyran-2-ylmethyl]-1H-indazol-3-yl}-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}- 2,2-dimethylpropanoic acid 580 134AA I-42A IC

3-{2-[4-amino-2-{6- fluoro-1-[tetrahydro-2H- pyran-2-ylmethyl]-1H-indazol-3-yl}-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}- 2,2-dimethylpropanoic acid 564 134AB I-42A IC

3-{2-[4-amino-2-{6- fluoro-1-[tetrahydro-2H- pyran-2-ylmethyl]-1H-indazol-3-yl}-5-methyl-6- oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}- 2,2-dimethylpropanoic acid 564 135A I-54 IA

4-(2-{4-amino-2-[6- fluoro-1-(3-fluorobenzyl)- 1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2- difluorobutanoic acid 596 136AA I-35A AD-H

(5S)-3-{2-[4-amino-2-{6- fluoro-1-[4- methylcyclohexylmethyl]-1H-indazol-3-yl}-5- methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3- thiazol-4-yl}-2,2- dimethylpropanoic acid 592136AB I-35A AD-H

(5S)-3-{2-[4-amino-2-{6- fluoro-1-[4- methylcyclohexylmethyl]-1H-indazol-3-yl}-5- methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3- thiazol-4-yl}-2,2- dimethylpropanoic acid 592137AA I-42A Racemic C18

3-{2-[4-amino-2-{6- fluoro-1-[4- methylcyclohexylmethyl]-1H-indazol-3-yl}-5- methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3- oxazol-4-yl}-2,2- dimethylpropanoic acid 576137AB I-42A Racemic C18

3-{2-[4-amino-2-{6- fluoro-1-[4- methylcyclohexylmethyl]-1H-indazol-3-yl}-5- methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3- oxazol-4-yl}-2,2- dimethylpropanoic acid 576 138BI-73 (R,R) WHELK- O 1

3-(2-{4-amino-2-[6- chloro-1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5-cyclopropyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2- dimethylpropanoic acid 616 139B I-73 (R,R) WHELK- O 1

3-(2-{4-amino-5- cyclopropyl-2-[6-fluoro-1- (2-fluorobenzyl)-1H-indazol-3-yl]-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2- dimethylpropanoic acid 600

Example 140A3-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropanoicacid

Step A—Ethyl3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropanoate

A mixture containing I-60 (460 mg, 1.273 mmol), I-A15 (432 mg, 1.273mmol) and potassium bicarbonate (637 mg, 6.36 mmol) in t-BuOH (10 ml) ina flask was stirred at 70° C. for 48 hours. The reaction was dilutedwith water and extracted with EtOAc (3×). The organic layers werecombined, washed with brine, dried over anhydr. MgSO₄, and filtered. Thefiltrate was concentrated in vacuo. The residue was purified by silicagel column chromatography with (EtOAc:EtOH 3:1): hexane to afford thetitle compound. m/z=418 (M+1).

StepB—3-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropanoicacid

A flask, containing ethyl3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2,2-dimethylpropanoate(470 mg, 0.760 mmol) and LiOH (91 mg, 3.80 mmol) in a mixture of MeCN (5ml) and water (5 ml) was stirred at 40° C. for 3 hours. The mixture wascooled to RT, diluted with EtOAc and aq. sat. KH₂PO₄, extracted withEtOAc, the organic layers were combined, washed with brine, dried overanhydr. MgSO₄, and filtered. The filtrate was concentrated in vacuo. toafford the racemic title compound Ex-140. The racemic material wasresolved using chiral SFC (CHIRALPAK® AD) to afford isomer Ex-140A(faster eluting) and isomer Ex-140B (slower eluting). ¹H NMR (400 MHz,DMSO-d₆) δ 12.73 (s, 1H), 11.25 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.01(d, J=1.7 Hz, 1H), 7.91 (s, 1H), 7.36 (t, J=7.0 Hz, 1H), 7.29 (dd,J=8.7, 1.8 Hz, 1H), 7.27-7.20 (m, 1H), 7.19-7.10 (m, 2H), 6.73 (s, 2H),5.81 (s, 2H), 4.48 (s, 2H), 1.24 (s, 3H), 1.07 (d, J=15.1 Hz, 6H),m/z=590 (M+1).

Example 141A2-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoicacid

Ex-141A was prepared following essentially the same procedure describedin Ex-140A, using I-61 as starting material. The racemic material wasresolved using chiral SFC (CHIRALCEL® OZ) to afford isomer Ex-141A(faster eluting) and isomer Ex-141B (slower eluting).

Examples 142B-219A

Using essentially the same procedure as described in Example 9B, Ex-10Band Ex-11B, the following compounds in Table 19 were prepared.

TABLE 19 Int. m/z Ex. SM Structure Name (M + 1) 142B I-65B

3-(4-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-2-yl)-2,2-dimethylpropanoic acid 606 143B I-74B

4-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}pyridinc-2-carboxylic acid 544 144A I-63A

3-(4-{4-amino-5-methyl-6-oxo-2-[1- (3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-pyrazol-1-yl)- 2,2-dimethylpropanoic acid 594 145AI-63A

3-(4-{4-amino-2-[1-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5h-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-pyrazol-1-yl)- 2,2-dimethylpropanoic acid 556 146AI-53A

4-(2-{4-amino-2-[1-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4- yl)benzoic acid 577 147A I-58A

4-(2-{4-amino-2-[1-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4- yl)benzoic acid 593 148A I-75A

3-(4-{4-amino-5-cyclopropyl-2-[1- (2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid 564 149A I-35A

(S)-3-(2-{4-amino-2-[1-(3- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)- 2,2-dimethylpropanoic acid 573 150AI-42A

3-(2-{4-amino-2-[1-(3- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)- 2,2-dimethylpropanoic acid 557 151AI-35A

(S)-3-(2-{4-amino-2-[1- (cyclohexylmethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5- methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2-dimethylpropanoicacid 561 152A I-42A

3-(2-{4-amino-2-[1- (cyclohexylmethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5- methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3- oxazol-4-yl)-2,2-dimethylpropanoicacid 545 153A I-35A

(S)-3-(2-{4-amino-2-[1- (cyclopentylmethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5- methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3- thiazol-4-yl)-2,2-dimethylpropanoicacid 547 154A I-42A

3-(2-{4-amino-2-[1- (cyclopentylmethyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5- methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3- oxazol-4-yl)-2,2-dimethylpropanoicacid 531 155B I-48B

4-{4-amino-2-[6-chloro-1-(3,3,4,4,4- penlafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl}benzoicacid 581 156A I-58A

4-(2-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4- yl)benzoic acid 664 157A I-76A

(2E)-3-(4-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)prop-2- enoic acid 607 158A I-75A

3-(4-{4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-cyclopropyl-6-oxo- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid 635 159A I-42A

3-(2-{4-amino-2-[6-chloro-1- (cyclohexylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 578 160B I-11B

(S)-3-(4-{4-amino-2-[6-chloro-1- (cyclopentylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid 545 161A I-42A

3-(2-{4-amino-2-[6-chloro-1- (cyclopentylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 564 162A I-35A

(S)-3-(2-{4-amino-2-[6-chloro-1- (cyclopentyknethyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic acid 580 163B I-11B

(S)-3-{4-[4-amino-2-{6-chloro-1- [(3,3-difluorocyclobutyl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}propanoic acid 567 164A I-53A

4-(2-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)benzoic acid 610 165A I-58A

4-(2-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)benzoic acid 626 166A I-59A

4-(2-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylbutanoic acid 620 167B I-55B

4-(2-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylbutanoic acid 604 168B I-66B

2-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-benzoxazole-5-carboxylic acid 584 169B I-37B

3-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl}benzoic acid543 170B I-56B

3-(2-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-5-methyl-1,3-oxazol-4-yl)-2,2- dimethylpropanoic acid 604 171A I-63A

3-(4-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropanoic acid 589 172A I-57A

3-(2-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-D-alanine 577 173A I-42A

3-(2-{4-amino-2-[6-chloro-1-(4- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 590 174A I-35A

(S)-3-(2-{4-amino-2-[6-chloro-l-(4- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic acid 606 175A I-42A

3-(2-{4-amino-2-[6-chloro-1-(3- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 590 176B I-56B

3-(2-{4-amino-2-[6-chloro-1-(3- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-5-methyl-1,3-oxazol-4-yl)-2,2- dimethylpropanoic acid 604 177B I-55B

4-(2-{4-amino-2-[6-chloro-1-(3- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylbutanoic acid 604 178A I-42A

3-(2-{4-amino-2-[6-chloro-1-(2,4- difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 608 179A I-35A

(S)-3-(2-{4-amino-2-[6-chloro-1- (2,4-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic acid 624 180A I-42A

3-(2-{4-amino-2-[6-chloro-1-(2,3- difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 608 181A I-35A

(S)-3-(2-{4-amino-2-[6-chloro-1- (2,3-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic acid 624 182A I-42A

3-(2-{4-amino-2-[6-chloro-1-(2,6- difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 608 183A I-35A

(S)-3-(2-{4-amino-2-[6-chloro-1- (2,6-difluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic acid 624 184A I-42A

3-{2-[4-amino-2-{6-chloro-1-[(3- fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}- 2,2-dimethylpropanoic acid 591 185AI-35A

(S)-3-{2-[4-amino-2-{6-chloro-1- [(3-fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-thiazol-4-yl}- 2,2-dimethylpropanoic acid 607 186AI-42A

3-(2-{4-amino-2-[6-chloro-1-(3- methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 586 187A I-42A

3-(2-{4-amino-2-[6-chloro-1-(2- fluoro-3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2- dimethylpropanoic acid 604 188A I-35A

(S)-3-(2-{4-amino-2-[6-chloro-1-(2- fluoro-3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2- dimethylpropanoic acid 620 189A I-42A

3-(2-{4-amino-2-[6-chloro-1-(2,3,6- trifluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 626 190A I-35A

(S)-3-(2-{4-amino-2-[6-chloro-1- (2,3,6-trifluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2- dimethylpropanoic acid 642 191B I-37B

3-{4-amino-2-[6-fluoro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl}benzoic acid527 192A I-63A

3-(4-{4-amino-2-[6-fluoro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1H-pyrazol-1-yl)-2,2-dimethylpropanoic acid 573 193B I-55B

4-(2-{4-amino-2-[6-fluoro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylbutanoic acid 588 194A I-35A

(S)-3-(2-{4-amino-2-[6-fluoro-1-(3- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylpropanoic acid 590 195A I-42A

3-(2-{4-amino-2-[6-fluoro-1-(3- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 574 196A I-59A

4-(2-{4-amino-2-[6-fluoro-1-(3- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylbutanoic acid 604 197B I-55B

4-(2-{4-amino-2-[6-fluoro-1-(3- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylbutanoic acid 588 198B I-56B

3-(2-{4-amino-2-[6-fluoro-1-(3- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-5-methyl-1,3-oxazol-4-yl)-2,2- dimethylpropanoic acid 588 199A I-35A

(S)-3-(2-{4-amino-2-[1-(2,3- difluorobenzyl)-6-fluoro-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)- 2,2-dimethylpropanoic acid 608 200AI-42A

3-(2-{4-amino-2-[1-(2,3- difluorobenzyl)-6-fluoro-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)- 2,2-dimethylpropanoic acid 592 201AI-35A

(5)-3-(2-{4-amino-2-[1- (cyclohexylmethyl)-6-fluoro-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)- 2,2-dimethylpropanoic acid 578 202AI-42A

3-(2-{4-amino-2-[1- (cyclohexylmethyl)-6-fluoro-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)- 2,2-dimethylpropanoic acid 562 203BI-34B

(2-{4-amino-2-[1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3-oxazol-4- yl)aceticacid 514 204A I-59A

4-(2-{4-amino-2-[1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-2,2-dimethylbutanoic acid 586 206B I-55B

4-(2-{4-amino-2-[1-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)- 2,2-dimethylbutanoic acid 571 207BI-55B

4-{2-[4-amino-2-{6-chloro-1-[(3- fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol-4-yl}- 2,2-dimethylbutanoic acid 605 208AI-42A

3-(2-{4-amino-2-[6-chloro-1-(3,3- dimethylbutyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 566 209B I-48B

4-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5- yl}benzoic acid543 210B I-11B

(S)-3-(4-{4-amino-2-[1-(3,3- dimethylbutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanoic acid 515 211A I-63A

3-(4-{4-amino-2-[6-fluoro-1-(2- fluoro-3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-pyrazol-1-yl)-2,2- dimethylpropanoic acid 587 212A I-42A

3-(2-{4-amino-2-[6-fluoro-1-(2- fluoro-3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2- dimethylpropanoic acid 588 213A I-42A

3-(2-{4-amino-2-[6-chloro-1-(2- fluoro-5-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}1,3-oxazol-4-yl)-2,2- dimethylpropanoic acid 604 214A I-35A

(S)-3-(2-{4-amino-2-[6-chloro-1-(2- fluoro-5-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro- 5H-pyrrolo[2,3-d]pyrimidin-5-yl}1,3-thiazol-4-yl)-2,2- dimethylpropanoic acid 620 215A I-42A

3-(2-{4-amino-2-[6-chloro-1-((3- fluoro-4-methylpyridin-2-yl)methyl)-1H-indazol-3-yl]-5- methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}1,3- oxazol-4-yl)-2,2-dimethylpropanoicacid 605 216A I-35A

(S)-3-(2-{4-amino-2-[6-chloro-1-((3- fluoro-4-methylpyridin-2-yl)methyl)-1H-indazol-3-yl]-5- methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}1,3- thiazol-4-yl)-2,2-dimethylpropanoicacid 621 217A I-76A

(2E)-3-(4-{4-amino-2-[1-(2- fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)prop-2- enoic acid 536 218A I-76A

(2E)-3-(4-{4-amino-2-[6-chloro-1- (2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)prop-2-enoic acid 509 219A I-51A

2-{4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}pyridine-4-carboxylic acid 544

Examples 220B-233A

Using essentially the same procedure as described in Example 76B, thefollowing compounds in Table 20 were prepared.

TABLE 20 Int. SM/ Chiral Resolution Step/ m/z Ex. Column Structure Name(M + 1) 220B I-55B/-

4-(2-{4-amino-2-[1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol- 4-yl)-2,2-dimethylbutanoic acid 570 221BI-11B/-

(S)-3-(4-{4-amino-2-[1-(4- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 537 222A I-35A/-

(S)-3-(2-{4-amino-2-[1-(3- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol- 4-yl)-2,2-dimethylpropanoic acid 572 223AI-42A/-

3-(2-{4-amino-2-[1-(3- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol- 4-yl)-2,2-dimethylpropanoic acid 556 224AI-35A/-

(S)-3-(2-{4-amino-5-methyl-6- oxo-2-[1-(2,3,6-trifluorobenzyl)-1H-indazol-3- yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}- 1,3-thiazol-4-yl)-2,2- dimethylpropanoicacid 608 225B I-11B/-

(S)-3-(4-{4-amino-5-methyl-2- [1-(3-methylbenzyl)-1H-indazol-3-yl]-6-oxo-6,7- dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 533 226A I-42A/-

3-(2-{4-amino-5-methyl-2-[1- (3-methylbenzyl)-1H-indazol-3-yl]-6-oxo-6,7-dihydro-5H- pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2- dimethylpropanoic acid 552 227B II-11B/-

(S)-3-(4-{4-amino-2-[1- (cyclopentylmethyl)-1H-indazol-3-yl]-5-methyl-6-oxo- 6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}phenyl)propanoic acid 511 228A I-42A/-

3-(2-{4-amino-2-[1- (cyclohexylmethyl)-1H- indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl}-1,3-oxazol-4-yl)-2,2-dimethylpropanoic acid 544 229AA I-35A/Step B/IC

(5S)-3-{2-[4-amino-5-methyl- 6-oxo-2-{1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol- 3-yl}-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]- 1,3-thiazol-4-yl}-2,2- dimethylpropanoicacid 562 229AB I-35A/Step B/IC

(5S)-3-{2-[4-amino-5-methyl- 6-oxo-2-{1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol- 3-yl}-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]- 1,3-thiazol-4-yl}-2,2- dimethylpropanoicacid 562 230AA I-42A/Step B/IC

3-{2-[4-amino-5-methyl-6-oxo- 2-{1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol-3-yl}- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol- 4-yl}-2,2-dimethylpropanoic acid 546 230ABI-42A/Step B/IC

3-{2-[4-amino-5-methyl-6-oxo- 2-{1-[tetrahydro-2H-pyran-2-ylmethyl]-1H-indazol-3-yl}- 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol- 4-yl}-2,2-dimethylpropanoic acid 546 231AAI-42A/Step B/Chiral Cellulose- SB

3-{2-[4-amino-5-methyl-2-{1- [-4-methylcyclohexylmethyl]-1H-indazol-3-yl}-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol- 4-yl}-2,2-dimethylpropanoic acid 558 231ABI-42A/Step B/Chiral Cellulose- SB

3-{2-[4-amino-5-methyl-2-{1- [4-methylcyclohexylmethyl]-1H-indazol-3-yl}-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl]-1,3-oxazol- 4-yl}-2,2-dimethylpropanoic acid 558 232BI-11B/-

(S)-3-{4-[4-amino-2-{1-[(3- fluoropyridin-2-yl)methyl]-1H-indazol-3-yl}-5-methyl-6-oxo- 6,7-dihydro-5H-pyrrolo[2,3- d]pyrimidin-5-yl]phenyl}propanoic acid 538 233A I-42A/-

3-(2-{4-amino-2-[1-(2-fluoro- 3-methylbenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7- dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-oxazol- 4-yl)-2,2-dimethylpropanoic acid 570

Example 234B(S)-3-(2-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1,3-thiazol-4-yl)-D-alanine

Example 234B was prepared using essentially the same procedures to thosedescribed in example 77B, using I-40B as starting material and I-47 asthe bromoketone. ¹H NMR (300 MHz, CD₃OD): δ 8.48 (d, J=8.7 Hz, 1H), 7.89(s, 1H), 7.48 (s, 1H), 7.43-7.28 (m, 3H), 7.17-7.11 (m, 2H), 5.89 (s,2H), 4.38 (dd, J=7.2, 5.4 Hz, 1H), 3.51-3.32 (m, 2H), 2.00 (s, 3H);m/z=593 (M+1).

Example 235B3-(2-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-imidazol-4-yl)propanoicacid

Step A—tert-Butyl3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1-(4-methoxybenzyl)-1H-imidazol-4-yl)propanoate

A flask containing I-A15 (136 mg, 0.45 mmol), I-77 (180 mg, 0.38 mmol)and potassium bicarbonate (375 mg, 3.75 mmol) in t-BuOH (15 mL) wasstirred for 16 h at 80° C. then concentrated in vacuo. The residue waspurified by silica gel column chromatography with MeOH:DCM (0-10%) toafford the racemic title compound. The racemic material was resolvedusing Chiral HPLC (CHIRALPAK® IC) to afford isomer A (faster eluting)and isomer B (slower eluting).

StepB—3-(2-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1H-imidazol-4-yl)propanoicacid

A flask containing tert-butyl3-(2-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}-1-(4-methoxybenzyl)-1H-imidazol-4-yl)propanoateisomer B (70 mg, 0.095 mmol) and trifluoroacetic acid (3 mL) was stirredfor 16 h at 100° C. then concentrated in vacuo. The residue was purifiedby reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford thetitle compound. ¹H NMR (300 MHz, CD₃OD) δ 8.51 (d, J=8.7 Hz, 1H), 7.87(s, 1H), 7.41-7.28 (m, 4H), 7.17-7.12 (m, 2H), 5.88 (s, 2H), 2.97 (t,J=6.9 Hz, 2H), 2.71 (t, J=6.9 Hz, 2H), 2.05 (s, 3H); m/z=561 (M+1).

Example 236A(S)-4-Amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-methyl-2-(2H-tetrazol-5-yl)propyl]thiazol-2-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

Step A—(S)-Ethyl3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoate

A flask, containing I-A40 (130 mg, 0.49 mmol), I-35A (183 mg, 0.49 mmol)and potassium bicarbonate (97 mg, 0.97 mmol) in t-BuOH (3 mL), wasstirred at 75° C. for 16 h then concentrated in vacuo to dryness. Theresidue was purified by silica gel chromatography using MeOH:DCM (0-5%)to afford the title product. m/z=600 (M+1)

StepB—(S)-3-(2-{4-Amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoicacid

To a flask containing (S)-ethyl3-(2{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoate(225 mg, 0.38 mmol) in MeOH (5 mL) and water (2.5 mL) at RT was addedLiOH (180 mg, 7.50 mmol). The mixture was stirred at RT for 16 h. To themixture was added HCl (7.5 mL, 1 N), and the solid was collected byfiltration, washed with water (20 mL) and dried in an oven to afford thetitle compound m/z=572 (M+1).

StepC—(S)-3-(2-{4-Amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanamide

To a flask containing(S)-3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanoicacid (190 mg, 0.33 mmol) and di-tert-butyl dicarbonate (160 mg, 0.731mmol) in DCM (3 mL) at RT was added pyridine (58 mg, 0.73 mmol) and theresulting mixture was stirred at RT for 2 h. To this was added ammoniumbicarbonate (79 mg, 0.99 mmol) and the mixture was stirred for 16 h atRT. The reaction was diluted with water, extracted with EtOAc (3×) andthe organic layers were combined, dried over anhydr. Na₂SO₄, filteredand the filtrate was concentrated in vacuo to dryness. To the residuewas added dichloromethane (4 mL) and TFA (2 mL). The mixture was stirredfor 2 h at RT before water (10 mL) was added, and the pH of the mixturewas adjusted to pH=7 with NaHCO₃. The resulting mixture was extractedwith DCM (3×), the organic layers were combined, dried over anhydr.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo to dryness.The residue was purified by silica gel chromatography using MeOH:DCM(0-5%) to afford the title product m/z=571 (M+1).

StepD—(S)-3-(2-{4-Amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanenitrile

To a flask, containing(S)-3-(2-{4-amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanamide(180 mg, 0.32 mmol) and pyridine (0.5 mL, 6.18 mmol) in DCM (5 mL) at 0°C. was added dropwise TFAA (0.5 mL, 3.54 mmol). The mixture was stirredfor 1 h at RT before MeOH (20 mL) was added and the mixture wasconcentrated in vacuo. The residue was diluted with water, and extractedwith EtOAc (3×). The organic layers were combined, dried over anhydr.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo to dryness.The residue was purified by silica gel chromatography using MeOH:DCM(0-5%) to afford the title product m/z=553 (M+1).

StepE—(S)-4-Amino-2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-methyl-2-(2H-tetrazol-5-yl)propyl]thiazol-2-yl}-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

A sealed tube containing(S)-3-(2-{4-amino-2[1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}thiazol-4-yl)-2,2-dimethylpropanenitrile(100 mg, 0.181 mmol), sodium azide (118 mg, 1.81 mmol) and ammoniumchloride (97 mg, 1.81 mmol) in DMA (3 mL) was stirred at 120° C. for 16h. The resulting mixture was filtered, and the filtrate was concentratedin vacuo. The residue was then purified by reverse phase HPLC (ACN/waterwith 0.05% NH₄HCO₃ modifier) to afford the title compound Ex-236A. ¹HNMR (300 MHz, CD₃OD) δ 8.69 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H),7.44 (dd, J=7.5, 7.5 Hz, 1H), 7.31-7.26 (m, 2H), 7.16-7.04 (m, 4H), 5.81(s, 2H), 3.22 (d, J=6.6 Hz, 2H), 1.76 (s, 3H), 1.52 (s, 3H), 1.48 (s,3H); m/z=596 (M+1).

Using essentially the same procedure as described in Ex-112B andEx-236A, the following compounds in Table 20 were prepared.

TABLE 20 Int. SM/ Chiral Resolution Step/ m/z Ex. Column Structure Name(M + 1) 237B I-11B/-

(S)-4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-5- {4-[2-(2H-tetrazol-5- yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 633 238A I-35A/-

(S)-4-amino-2-[6-chloro-1- (2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2- methyl-2-(2H-tetrazol-5-yl)propyl]-1,3-thiazol-2-yl}- 5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one 630 239A I-42A/-

4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-methyl- 2-(2H-tetrazol-5-yl)propyl]-1,3-oxazol-2-yl}-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 614 240BI-11B/-

(S)-4-amino-2-[1-(2- fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5-{4-[2-(2H- tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 562 241A I-35A/-

(S)-4-amino-2-[1-(2- fluorobenzyl)-1H- pyrazolo[3,4-b]pyridin-3-yl]-5-methyl-5-{4-[2-methyl-2- (2H-tetrazol-5-yl)propyl]-1,3-thiazol-2-yl}-5,7- dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 597242B I-11B/-

(S)-4-amino-2-[1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(2H- tetrazol-5-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 561 243A I-51A/-

5-[4-(2H-tetrazol-5- yl)pyridin-2-yl]-4-amino-2-[6-chloro-1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 568 244A I-78A/-

5-{4-[(2H-tetrazol-5- yl)methyl]phenyl}-4-amino- 2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3- yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin- 6-one 581 245B I-11B/-

(S)-5-{4-[2-(2H-tetrazol-5- yl)ethyl]phenyl}-4-amino-2-{1-[(3-fluoropyridin-2- yl)methyl]-1H-indazol-3-yl}-5-methyl-5,7-dihydro-6H- pyrrolo[2,3-d]pyrimidin-6- one 562 246AI-62/Step D/IA

5-{5-[2-(2H-tetrazol-5- yl)ethyl]pyridin-2-yl}-4-amino-2-[1-(2-fluorobenzyl)- 1H-indazol-3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 562 247A I-62/Step D/IA

5-{5-[2-(2H-tetrazol-5- yl)ethyl]pyridin-2-yl}-4-amino-2-[6-chloro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5,7-dihydro- 6H-pyrrolo[2,3-d]pyrimidin- 6-one 596

Example 248B4-Amino-2-[-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-methyl-2-(2H-tetrazol-5-yl)propyl]oxazol-2-yl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

A flask containing Ex-239A (60 mg, 0.098 mmol) an palladium on carbon(80 mg, 0.068 mmol, 10 w %) in MeOH (2 mL) was evacuated and flushed(3×) with nitrogen, followed by flushing with hydrogen. The mixture wasstirred for 5 h at RT under an atmosphere of hydrogen (1.5 atm). Thepalladium on carbon was filtered out and washed with MeOH (3×), EtOAc(3×), and DCM (3×). The combined filtrate was concentrated in vacuo. Theresidue was then purified by reverse phase HPLC (ACN/water with 0.05%NH₄HCO₃ modifier) to afford the title compound ¹H NMR (300 MHz, CD₃OD) δ8.68 (d, J=8.4 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.41 (dd, J=7.2, 7.2 Hz,1H), 7.32-7.23 (m, 2H), 7.14-7.00 (m, 4H), 5.78 (s, 2H), 2.91 (d, J=8.7Hz, 2H), 1.83 (s, 3H), 1.43 (s, 3H), 1.40 (s, 3H); m/z=580 (M+1).

Example 249B4-Amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-[3-(1H-tetrazol-5-yl)phenyl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

StepA—3-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile

A flask containing I-A23 (126 mg, 0.44 mmol), I-69B (98 mg, 0.37 mmol)and potassium bicarbonate (110 mg, 1.10 mmol) in t-BuOH (1.8 mL) wasstirred at 80° C. for 16 h. The mixture was then concentrated in vacuoto dryness. The residue was purified by silica gel chromatography using(EtOAc:EtOH 3:1):Hexane (0-30%) to afford the title product.

StepB—4-Amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-[3-(1H-tetrazol-5-yl)phenyl]-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

To a flask containing3-{4-amino-2-[6-fluoro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzonitrile(120 mg, 0.24 mmol) in toluene (1 mL) was added dibutyltin oxide (6.0mg, 0.02 mmol) and TMS azide (0.06 mL, 0.47 mmol). The resulting mixturewas stirred at 130° C. for 2 days, and then concentrated in vacuo. Theresidue was purified by reverse phase HPLC (ACN/water with 0.05% formicacid modifier) to afford the title compound Ex-249B. ¹H NMR (500 MHz,DMSO-d₆): δ 11.15 (s, 1H), 8.74 (dd, J=10 Hz, 5 Hz, 1H), 7.95-7.88 (m,2H), 7.68 (dd, J=10 Hz, 5 Hz, 1H), 7.49-7.08 (m, 7H), 6.57 (br s, 2H),5.77 (s, 2H), 1.83 (s, 3H); m/z=551 (M+1).

Using essentially the same procedure described in Example 249B, thefollowing compounds in Table 21 were prepared

TABLE 21 Int. SM/ Chiral Resolution Step/ m/z Ex. Column Structure Name(M + 1) 250B I-70B/-

4-amino-2-[6-fluoro-1-(2- fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-[4-(1H- tetrazol-5-yl)phenyl]-5,7-dihydro-6H-pyrroio[2,3- d]pyrimidin-6-one 551 251B I-69/Step B/AS

4-amino-2-[6-chloro-1- (3,3,4,4,4-pentafluorobutyl)-1H-indazol-3-yl]-5-methyl-5- [3-(1H-tetrazol-5-yl)phenyl]-5,7-dihydro-6H-pyrrolo[2,3- d]pyrimidin-6-one 605 252B I-69/Step B/AS

4-amino-5-methyl-2-[1- (3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3- yl]-5-[3-(2H-tetrazol-5-yl)phenyl]-5,7-dihydro-6H- pyrrolo[2,3-d]pyrimidin-6-one 572 253AI-72/Step A/IA

5-[6-(2H-tetrazol-5-yl)pyridin- 2-yl]-4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol- 3-yl]-5-methyl-5,7-dihydro-6H-pyrrolo[2,3-d]pynmidin-6- one 568

Example 254A6-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyridine-3-carboxylicacid

StepA—6-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}nicotinonitrile

A flask containing I-71A (89 mg, 0.33 mmol), I-A15 (100 mg, 0.33 mmol)and potassium bicarbonate (49 mg, 0.49 mmol) in t-BuOH (5 mL) wasstirred for 16 h at 70° C., and then concentrated in vacuo. The residuewas purified by silica gel column chromatography with MeOH:DCM (0-10%)to afford the title compound.

Step B—Methyl6-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}nicotinate

To a flask containing6-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}nicotinonitrile(120 mg, 0.23 mmol) in MeOH (10 mL) at RT was added dropwise sulfurousdichloride (3 mL). The resulting mixture was stirred for 16 h at 80° C.then concentrated in vacuo. To the residue was added aq. sat. NaHCO₃ andextracted with EtOAc (3×). The organic layers were combined, washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with MeOH:DCM (0-10%) to afford the title compound.

StepC—6-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}nicotinicacid

A flask containing methyl6-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}nicotinate(90 mg, 0.16 mmol), lithium hydroxide (1.6 mL, 1 M in water, 1.6 mmol)in MeOH (5 mL) was stirred for 16 h at RT, and then concentrated invacuo. Water (3 mL) and hydrogen chloride (1 N, 1.6 mL) were added. Theresulting solid was collected by filtration and washed with water (3×).The residue was purified by reverse phase HPLC (ACN/water with 0.05% TFAmodifier) to afford the title compound Ex-254A. ¹H NMR (300 MHz, CD₃OD)δ 9.11 (d, J=1.5 Hz, 1H), 8.67 (d, J=8.7 Hz, 1H), 8.28 (dd, J=8.1, 2.1Hz, 1H), 7.64 (s, 1H), 7.49 (d, J=8.1H, 1H), 7.37-7.29 (m, 1H), 7.25(dd, J=8.7, 1.5 Hz, 1H), 7.18-7.07 (m, 3H), 5.77 (s, 2H), 1.92 (s, 3H);m/z=544 (M+1).

Example 255A6-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}picolinicacid

StepA—6-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}picolinonitrile

A flask containing I-72 (430 mg, 1.60 mmol), I-A15 (510 mg, 1.68 mmol)and potassium bicarbonate (802 mg, 8.01 mmol) in t-BuOH (10 mL) wasstirred at 70° C. for 16 h. The reaction mixture was concentrated invacuo. The residue was purified by silica gel column chromatography withMeOH:DCM (0-10%) to afford the title racemic compound. The racemicmaterial was resolved using Chiral HPLC (CHIRALPAK® IA) to afford isomerA (faster eluting) and isomer B (slower eluting).

Step B—Methyl6-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}picolinate

To a flask containing6-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}picolinonitrileisomer A (40 mg, 0.076 mmol) in MeOH (10 mL) at RT was added dropwisesulfurous dichloride (1 mL, 13.70 mmol). The resulting mixture wasstirred for 16 h at 80° C., and then the mixture was concentrated invacuo. The residue was diluted with aq. sat. NaHCO₃ and extracted withEtOAc (3×). The organic layers were combined, washed with brine, driedover anhydr. Na₂SO₄, and filtered. The filtrate was concentrated invacuo. The residue was purified by silica gel column chromatography withMeOH:DCM (0-10%) to afford the title compound.

StepC—6-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}picolinicacid

A flask containing methyl6-(4-amino-2-(6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)picolinate(40 mg, 0.072 mmol) and lithium hydroxide (69 mg, 2.87 mmol) in amixture of water (1.5 mL): THF (1.5 mL) was stirred for 16 h at RT. Tothis was added hydrochloric acid (28.7 mL, 0.1 N). The solid wascollected by filtration, washed with water (2×5 mL), and dried in anoven to afford the title compound Ex-255A. ¹H NMR (300 MHz, CD₃OD) δ8.65 (d, J=8.7 Hz, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.99 (dd, J=7.8, 7.8 Hz,1H), 7.71 (d, J=7.8 Hz, 1H), 7.64 (s, 1H), 7.36-7.22 (m, 2H), 7.17-7.06(m, 3H), 5.76 (s, 2H), 1.91 (s, 3H); m/z=544 (M+1).

Example 256B(S)-4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5-{4-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]phenyl}-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one

StepA—(S)-3-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamide

To a flask containing Ex-47B (1.0 g, 1.58 mmol) in DMF (10 mL) was addeddi(1H-imidazol-1-yl)methanone (1.28 g, 7.88 mmol). The mixture wasstirred at RT for 30 min before ammonium chloride (0.17 g, 3.15 mmol)was added. The resulting mixture was stirred at RT for 16 h, thendiluted with water, and extracted with EtOAc (3×). The organic layerswere combined, dried over anhydr. Na₂SO₄, filtered, and the filtrate wasconcentrated in vacuo to dryness. The residue was purified by silica gelchromatography using MeOH:DCM (0-5%) to afford the title product, m/z570 (M+1).

StepB—(S)-3-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanenitrile

To a flask containing(S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanamide(0.8 g, 1.40 mmol) and pyridine (0.5 mL, 6.18 mmol) in DCM (5 mL) at 0°C., was added dropwise TFAA (0.5 mL, 3.54 mmol). The mixture was stirredat RT for 1 h. The mixture was diluted with MeOH and concentrated invacuo. The residue was diluted with water, extracted with EtOAc (3×).The organic layers were combined, washed with brine, dried over anhydr.Na₂SO₄, and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography with MeOH:DCM(0-5%) to afford the title compound. m/z=552 (M+1).

StepC—(S)-3-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl}-N-hydroxypropanimidamide

A flask, containing(S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)propanenitrile(150 mg, 0.272 mmol) and aqueous hydroxylamine (7.5 mL, 0.272 mmol, 50%)in EtOH (7.5 mL) was stirred at 30° C. for 16 h. The mixture wasconcentrated in vacuo and the residue was lyophilized to afford thetitle compound m/z=585 (M+1).

StepD—(S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenethyl)-1,2,4-oxadiazol-5(4H)-one

A flask containing(S)-3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-N-hydroxypropanimidamide(120 mg, 0.21 mmol), di(1H-imidazol-1-yl)methanone (332 mg, 2.05 mmol)in THF (12 mL) was stirred at RT for 16 h and at 50° C. for 24 h. Themixture was concentrated in vacuo, and aq. sat. NaHCO₃ was added to theresidue. The mixture was extracted with EtOAc (3×). The organic layerswere combined, washed with brine, dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography with MeOH:DCM (0-10%) thenby reverse phase HPLC (ACN/water with 0.05% TFA modifier) to afford thetitle compound Ex-256B. ¹H NMR (300 MHz, CD₃OD) δ 8.65 (d, J=8.7 Hz,1H), 7.62 (s, 1H), 7.33-7.21 (m, 6H), 7.15-7.04 (m, 3H), 4.84 (s, 2H),2.94 (t, J=7.2 Hz, 2H), 2.78 (t, J=7.2 Hz, 2H), 1.98 (s, 3H); m/z=611(M+1).

Example 257A[2-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)ethyl]phosphonicacid

StepA—4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-[4-(diethoxymethyl)phenyl]-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

A flask containing I-A15 (200 mg, 0.66 mmol), I-49 (228 mg, 0.66 mmol)and potassium bicarbonate (79 mg, 0.79 mmol) in t-BuOH (4 mL) wasstirred at 70° C. for 16 h. The reaction mixture was concentrated invacuo to dryness to afford the title compound. m/z=601 (M+1).

StepB—4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzaldehyde

To a flask containing4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-[4-(diethoxymethyl)phenyl]-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one(250 mg, 0.25 mmol) in DCM (10 ml) at RT was added TFA (1 mL) dropwise.The resulting mixture was stirred for 16 h at RT then concentrated invacuo, diluted with EtOAc, washed with aq. sat. NaHCO₃, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography withMeOH:DCM (0-10%) to afford the title compound. m/z=527 (M+1).

Step C—Diethyl4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}styrylphosphonate

A flask containing4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzaldehyde(120 mg, 0.228 mmol), diethyl((triphenylphosphoranylidene)methyl)phosphonate (470 mg, 1.139 mmol),(prepared following J. Org. Chem., 1996, 61 (22), 7697) in a DMF (2 mL):toluene (10 mL) mixture was stirred at 90° C. for 16 h. The reaction wasdiluted with EtOAc, washed with brine, dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography with MeOH:DCM (0-10%) toafford the title compound. m/z=661 (M+1).

Step D—Diethyl4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenethylphosphonate

A flask, containing diethyl4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}styrylphosphonate(65 mg, 0.098 mmol), sodium acetate (40 mg, 0.492 mmol) and4-methylbenzenesulfonhydrazide (55 mg, 0.295 mmol) in a1,2-dimethoxyethane (20 mL): water (2 mL) mixture was stirred at 80° C.for 16 h. The reaction was diluted with water, extracted with EtOAc(3×). The organic layers were combined, washed with brine, dried overanhydr. Na₂SO₄, and filtered. The filtrate was concentrated in vacuo.The residue was purified by silica gel column chromatography withMeOH:DCM (0-10%) to afford racemic title product. The racemic materialwas resolved using Chiral HPLC (CHIRALPAK® IA) to afford isomer A(faster eluting) and isomer B (slower eluting). m/z=663 (M+1).

StepE—4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenethylphosphonicacid

To a flask containing diethyl4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenethylphosphonateisomer A (25 mg, 0.038 mmol) in DCM (20 mL) at 0° C. was added dropwisebromotrimethylsilane (2 mL). The resulting mixture was stirred for 5days at RT. The mixture was concentrated in vacuo, and diluted with MeOH(2 mL). The resulting mixture stirred at RT for 30 min. The mixture wasthen concentrated in vacuo, and the residue was purified by reversephase HPLC (ACN/water with 0.05% TFA modifier) to afford the titlecompound Ex-257A. ¹H NMR (300 MHz, CD₃OD) δ 8.56 (d, J=8.7 Hz, 1H), 7.79(s, 1H), 7.43-7.21 (m, 6H), 7.19-7.08 (m, 3H), 5.82 (s, 2H), 2.91-2.82(m, 2H), 1.99-1.88 (m, 2H), 1.81 (s, 3H); m/z=607 (M+1).

Example 258B2-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)ethanesulfonicacid

Step A—Ethyl2-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)ethenesulfonate

To a flask under an inert atmosphere of nitrogen, containing ethyl(diethoxyphosphoryl) methanesulfonate (3.46 g, 13.28 mmol) in THF (70mL) at −78° C. was added dropwise n-butyllithium (4.3 mL, 10.63 mmol,2.5 M in hexane). The resulting mixture was stirred for 30 min at −78°C. before4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}benzaldehyde(700 mg, 1.33 mmol) was added, and the resulting mixture was stirred for16 h at RT. The reaction was quenched by the addition of aq. sat. NH₄Cl,extracted with EtOAc (3×). The organic layers were combined, washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with MeOH:DCM (0-10%) to afford the title compoundm/z=633 (M+1).

StepB—2-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)ethanesulfonicacid

A flask, containing ethyl2-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)ethenesulfonate(750 mg, 1.19 mmol), sodium acetate (1.46 g, 17.77 mmol),4-methylbenzenesulfonhydrazide (2.20 mg, 11.85 mmol) in a1,2-dimethoxyethane (100 mL): water (20 mL) mixture was stirred at 80°C. for 6 h. The reaction was diluted with water, extracted with EtOAc(3×). The organic layer was washed with brine, dried over anhydr.Na₂SO₄, filtered and the filtrate was concentrated in vacuo. The residuewas purified by reverse phase HPLC (ACN/water) to afford the titleracemic compound Ex-258. The racemic material was resolved using chiralSFC (CHIRALPAK® IC) to afford isomer Ex-258A (faster eluting) and isomerEx-258B (slower eluting). ¹H NMR (300 MHz, CD₃OD) δ 8.71 (d, J=8.7 Hz,1H), 7.68 (d, J=1.5 Hz, 1H), 7.41-7.30 (m, 6H), 7.27-7.10 (m, 3H), 5.81(s, 2H), 3.13-3.00 (m, 4H), 1.89 (s, 3H); m/z=607 (M+1).

Example 259B(S)-3-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenyl)-N-(methylsulfonyl)propanamide

A flask containing Ex-47B (100 mg, 0.17 mmol), 4-dimethylaminopyridine(26 mg, 0.21 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (47 mg, 0.24 mmol) in DMF (16 mL) was stirred at RT for 30min before methanesulfonamide (50 mg, 0.52 mmol) was added. Theresulting mixture was stirred for 16 h at RT. The reaction was quenchedby the addition of water, and extracted with EtOAc (3×). The organiclayer was washed with brine, dried over anhydr. Na₂SO₄, filtered, andthe filtrate was concentrated in vacuo. The residue was purified bysilica gel column chromatography with MeOH:DCM (0-8%). The residue waspurified by reverse phase HPLC (ACN/water with 0.05% NH₄HCO₃ modifier)to afford the title compound Ex-259B. ¹H NMR (CD₃OD, 400 MHz): δ 8.71(d, J=8.8 Hz, 1H), 7.68 (s, 1H), 7.39-7.26 (m, 6H), 7.20-7.11 (m, 3H),5.81 (s, 2H), 3.06 (s, 3H), 2.95 (t, J=7.2 Hz, 1H), 2.59 (t, J=7.2 Hz,2H), 1.89 (s, 3H); m/z=648 (M+1).

Example 260A(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy)aceticacid

StepA—4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-(4-methoxyphenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)

A flask, containing I-A15 (200 mg, 0.59 mmol), I-50A (161 mg, 0.59 mmol)and potassium bicarbonate (177 mg, 1.77 mmol) in t-BuOH (5 mL) wasstirred at 75° C. for 16 h. The reaction was quenched by the addition ofbrine, and extracted with EtOAc (3×). The organic layers were combined,washed with brine, dried over anhydr. Na₂SO₄, and filtered. The filtratewas concentrated in vacuo. The residue was purified by silica gel columnchromatography with MeOH:DCM (0-10%) to afford the title compoundm/z=529 (M+1).

StepB—4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-(4-hydroxyphenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

In a flask containing4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-(4-methoxyphenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)(255 mg, 0.48 mmol), and tribromoborane (1 mL) in DCM (5 mL) at 0° C.The resulting mixture was stirred at RT for 16 h. The reaction wasquenched by the addition of ice water. The pH of the resulting mixturewas adjusted to pH 8 with NaHCO₃, and the resulting mixture wasextracted with EtOAc (3×). The organic layers were combined, washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was dissolved with hydrobromic acid(40%, 8 mL), and stirred for 16 h at 80° C. The reaction was poured intoice water. The pH of the resulting solution was adjusted to pH 8 withNaHCO₃. extracted with EtOAc (3×). The organic layers were combined,washed with brine, dried over anhydr. Na₂SO₄, and filtered. The filtratewas concentrated in vacuo. The residue was purified by silica gel columnchromatography with MeOH:DCM (0-10%) to afford the title compoundm/z=515 (M+1).

Step C—Ethyl2-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy)acetate

To a flask wrapped in aluminum foil, were placed4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-(4-hydroxyphenyl)-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one(80 mg, 0.16 mmol), silver carbonate (880 mg, 3.20 mmol), and ethyl2-bromoacetate (7 mL) in acetonitrile (80 mL). The mixture was stirredat 80° C. for 16 h. The solid was filtered out and washed with dimethylsulfoxide (3×). The filtrate was concentrated in vacuo. The residue waspurified by reverse phase HPLC (ACN/water with 0.05% NH₄HCO₃ modifier)to afford the title compound. m/z=601 (M+1).

StepD—2-(4-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy)aceticacid

A flask containing ethyl2-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}phenoxy)acetate(55 mg, 0.09 mmol) and lithium hydroxide monohydrate (110 mg, 2.62 mmol)in a mixture of THF (4 mL): water (4 mL): MeOH (2 mL) was stirred at RTfor 16 h. The resulting mixture was concentrated in vacuo. The residuewas purified by reverse phase HPLC (ACN/water with 0.05% NH₄HCO₃modifier). The fractions were combined and concentrated in vacuo. The pHof the resulting solution was adjusted to pH 4 with hydrochloric acid (1N). The solid was collected by filtration, washed with water (2×), anddried in an oven to afford the title product Ex-260A. ¹H NMR (400 MHz,DMSO-d₆): δ 13.01 (brs, 1H), 11.07 (s, 1H), 8.71 (d, J=8.7 Hz, 1H), 8.01(d, J=1.2 Hz, 1H), 7.40-7.30 (m, 1H), 7.28 (dd, J=8.8, 1.4 Hz, 2H),7.18-7.14 (m, 4H), 7.87 (d, J=8.8 Hz, 2H), 6.60-6.50 (br, 2H), 5.81 (s,2H), 4.63 (s, 2H), 1.75 (s, 3H); m/z=573 (M+1).

Example 261C3-[1-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyrrolidin-3-yl]propanoicacid

Step A—Ethyl4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

A flask containing I-A15 (1 g, 2.95 mmol), I-30 (0.84 g, 3.54 mmol) andpotassium bicarbonate (1.47 g, 14.74 mmol) in t-BuOH (15 mL) was stirredat 70° C. for 16 h. The resulting mixture was concentrated in vacuo. DCMand MeOH were added to the residue, and solids were removed byfiltration. The filtrate was concentrated in vacuo, and the residue wasre-crystallized from EtOAc:petroleum ether. m/z=495 (M+1).

StepB—4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5H-pyrrol[2,3-d]pyrimidin-6(7H)-one

In a flask containing ethyl4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxylate(1.3 g, 2.63 mmol) in EtOH (50 mL) at 0° C. was added sodium hydroxide(6.6 mL, 13.2 mmol, 2 M) dropwise. The resulting mixture was stirred for10 min at 0° C. before the reaction was quenched by the addition of aq.sat. NH₄C,l and extracted with EtOAc (3×). The organic layers werecombined, washed with brine, dried over anhydr. Na₂SO₄, and filtered.The filtrate was concentrated in vacuo and the residue was purified bysilica gel column chromatography with EtOAc:petroleum ether to affordthe title compound. m/z=423 (M+1).

Step C—Ethyl3-(1-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyrrolidin-3-yl)propanoate

To a flask containing4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one(300 mg, 0.71 mmol) in DCM (10 mL) was added bromine (227 mg, 1.42mmol). The mixture was stirred at RT for 3 h before ethyl3-(pyrrolidin-3-yl)propanoate (1460 mg, 8.51 mmol) was added. Theresulting mixture was stirred for 2 h at RT, then quenched by theaddition of water, and extracted with EtOAc (3×). The organic layerswere combined, washed with brine, dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography with MeOH:DCM (0-10%) toafford the racemic title compound. The racemic material was resolvedusing Chiral HPLC (CHIRALPAK IA) to afford 4 peaks, isomer A (fastereluting), isomer B (second eluting), isomer C (third eluting), andisomer D (slower eluting). m/z=592 (M+1).

StepD—3-(1-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyrrolidin-3-yl)propanoicacid

A flask containing ethyl3-(1-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyrrolidin-3-yl)propanoateisomer C (47 mg, 0.079 mmol), and lithium hydroxide (2 mL, 2 M in water)in THF (6 mL) was stirred for 16 h at RT. The mixture was concentratedin vacuo, water (3 mL) and hydrogen chloride (2 mL, 2 M in water) wereadded to the residue. Solids were collected by filtration and washedwith water (3×) and dried to afford the title product Ex-261C. ¹H NMR(400 MHz, CD₃OD) δ 8.64 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.36-7.27 (m,2H), 7.17-7.08 (m, 3H), 5.79 (s, 2H), 3.48-3.30 (m, 1H), 3.27-2.98 (m,3H), 2.33-2.21 (m, 3H), 2.17-2.08 (m, 1H), 1.82 (s, 3H), 1.77-1.64 (m,2H), 1.58-1.53 (m, 1H); m/z=564 (M+1).

Example 261D3-[1-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyrrolidin-3-yl]propanoicacid

Example 261D was prepared using the same procedure as Ex-261C usingethyl3-(1-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}pyrrolidin-3-yl)propanoateisomer D as intermediate. m/z=564 (M+1).

Example 262B3-(1-{4-Amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}piperidin-4-yl)propanoicacid

Ex-262B was prepared using the same protocol as Ex-261C, coupling4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-onewith ethyl 3-(piperidin-4-yl)propanoate to afford racemic ethyl3-(4-{4-amino-2-[6-chloro-1-(2-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)propanoatewhich was resolved using Chiral HPLC (CHIRALPAK IC) to afford isomer A(faster eluting), and isomer B (slower eluting). Isomer B was used toprepare Ex-262B, m/z=578 (M+1)

Example 263AA3-(4-{4-Amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)propanoicacid

StepA—4-Amino-5-(4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

A flask containing I-A27 (0.8 g, 2.64 mmol), I-68 (1 g, 2.64 mmol) andpotassium bicarbonate (0.4 g, 3.96 mmol) in t-BuOH (20 mL) was stirredfor 16 h at 70° C. The reaction was quenched by the addition of waterand extracted with EtOAc (3×). The organic layers were combined, washedwith brine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with MeOH:DCM (0-10%) to afford the title compound.m/z=649 (M+1).

StepB—4-Amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-[4-(hydroxymethyl)cyclohexyl]-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

A flask containing4-amino-5-(4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one(0.61 g, 0.940 mmol), tetra-n-butylammonium fluoride (1.3 g, 4.97 mmol)in THF (20 mL) was stirred for 16 h at RT. The reaction was quenched bythe addition of brine and extracted with EtOAc (3×). The organic layerswere combined, washed with brine, dried over anhydr. Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo. The residue waspurified by silica gel column chromatography with EtOAc:petroleum ether(60-100%) to afford the title compound. m/z=535 (M+1).

StepC—4-(4-Amino-2-(6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)cyclohexanecarbaldehyde

To a flask under a inert atmosphere of nitrogen, containing DMSO (0.14mL, 1.97 mmol) and DCM (20 mL) at −78° C. was added dropwise oxalylchloride (0.14 mL, 1.65 mmol) in DCM (2 mL). The resulting mixture wasstirred at −78° C. for 30 min, before a solution of4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-[4-(hydroxymethyl)cyclohexyl]-5-methyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one(440 mg, 0.82 mmol) in DCM (2 mL) and DMSO (0.5 mL) was added dropwiseat −78° C. The resulting mixture was stirred for 2 h at −78° C., then asolution of triethylamine (0.57 mL, 4.11 mmol) in DCM (2 mL) was added.The resulting mixture was stirred for 30 min at −78° C., then warmed toRT over 30 min. The reaction was quenched by the addition of water andextracted with DCM (3×). The organic layers were combined, washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography with EtOAc:petroleum ether (60-100%) to afford the titlecompound. m/z=533 (M+1).

Step D—Ethyl3-(4-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)acrylate

To a flask containing ethyl 2-(diethoxyphosphoryl)acetate (1.75 g, 7.81mmol) in Et₂O (40 mL) at 0° C. was added sodium hydride (311 mg, 7.79mmol). The resulting mixture was stirred for 15 min at RT before asolution of4-(4-amino-2-(6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl)-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl)cyclohexanecarbaldehyde(415 mg, 0.779 mmol) in THF (6 mL) was added. The resulting mixture wasstirred for 2 h at RT before it was quenched by the addition of aq. sat.NH₄Cl, extracted with EtOAc (3×). The organic layer was washed withbrine, dried over anhydr. Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo. The residue was purified by reverse phase HPLC(ACN/water with 0.1% TFA modifier) to afford the title compound. m/z=603(M+1).

Step E—Ethyl3-(4-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)propanoate

A flask containing ethyl3-(4-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)acrylate(370 mg, 0.61 mmol), 4-methylbenzenesulfonohydrazide (472 mg, 2.53mmol), sodium acetate (347 mg, 4.23 mmol) in diethylene glycol dimethylether (10 mL) and water (1 mL) was stirred at 80° C. for 16 h. Thereaction was quenched by the addition of water, extracted with EtOAc(3×). The organic layer was washed with brine, dried over anhydr.Na₂SO₄, filtered, and the filtrate was concentrated in vacuo. Theresidue was purified by silica gel column chromatography withEtOAc:petroleum ether (0-10%). The residue was purified by reverse phaseHPLC (ACN/water with 0.05% TFA modifier). to afford isomer A (fastereluting), and isomer B (slower eluting). The racemic isomer A wasresolved using chiral SFC (CHIRALPAK IC) to afford isomer AA (fastereluting), isomer AB (slower eluting). m/z=605 (M+1).

StepF—3-(4-{-4-Amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)propanoicacid

A flask containing ethyl3-(4-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)propanoateisomer AA (34 mg, 0.056 mmol), lithium hydroxide hydrate (34 mg, 0.81mmol) in a THF (4 mL): water (3 mL) mixture was stirred at RT for 16 h.The reaction was quenched by the addition of hydrochloric acid (8.1 mL,0.1 N) extracted with EtOAc (3×). The organic layer was washed withbrine, dried over anhydr. Na₂SO₄, filtered, and the filtrate wasconcentrated in vacuo to afford the title compound Ex-263AA. ¹H NMR (400MHz, CD₃OD) δ 8.46 (d, J=8.4 Hz, 1H), 7.86 (s, 1H), 7.40-7.37 (m, 2H),7.19-7.02 (m, 3H), 5.87 (s, 2H), 2.27 (t, J=6.8 Hz, 2H), 2.07-1.84 (m,3H), 1.76-1.59 (m, 6H), 1.49-1.47 (m, 2H), 1.26-0.89 (m, 4H); m/z=577(M+1).

Example 263BA3-(4-{4-Amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)propanoicacid

Ethyl3-(4-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)propanoateisomer B prepared as in Ex-263AA was resolved using chiral SFC(CHIRALPAK IB) to afford isomer BA (faster eluting) and isomer BB(slower eluting). Ethyl3-(4-{4-amino-2-[6-chloro-1-(3-fluorobenzyl)-1H-indazol-3-yl]-5-methyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl)propanoateBA was hydrolysed to afford the title compound Ex-263BA.

Biological Assays:

Cell-Based sGC Functional Assay (Cyclic GMP Assay for sGC Activator:CASA Assay)

Soluble guanylate cyclase (sGC) is a heme-containing enzyme thatconverts GTP to secondary messenger cGMP. Increases in cGMP levelsaffect several physiological processes including vasorelaxation throughmultiple downstream pathways. The rate by which sGC catalyzes cGMPformation is greatly increased by NO and by recently discoveredNO-independent activators and stimulators. Heme-dependent activators(HDAs) preferentially activate sGC containing a ferrous heme group. Todetermine the effect of sGC activators on enzyme activity, the CASAassay was developed to monitor the generation of cGMP in a cell linethat stably expresses the heterodimeric sGC protein.

Methods:

A CHO-K1 cell line stably expressing the sGC α1/β1 heterodimer wasgenerated using a standard transfection protocol. CHO-K1 cells weretransfected with plasmids pIREShyghsGCα1 and pIRESneo-hsGCβ1simultaneously using FUGENE reagent. Clones that stably express bothsubunits were selected with hygromycin and neomycin for ˜2 weeks. Clone#7 was chosen for the assay and was designated CHO-K1/sGC. CHO-K1/sGCcells were maintained in F-K12 medium containing 10% heat-inactivatedFetal Bovine Serum (FBS), 100 g/mL penicillin/streptomycin, 0.5 mg/mLhygromycin and 0.25 mg/mL G418. The cells were then cryopreserved inLN2. On the day of the assay, the cells were thawed and resuspended inEBSS Assay Buffer (Sigma, E3024) supplemented with 5 mM MgCl₂, 10 mMHEPES (4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid) and 0.05% BSA(bovine serum albumin) (EAB) and cell density was then adjusted to2.25×105/mL with EAB. IBMX (3-isobutyl-1-methylxanthin, 0.5 mM) wasadded to inhibit degradation of cGMP. Compounds were diluted from DMSOstock solutions and added to the assay at a final DMSO concentration of2.5%. Cells were pre-incubated in the presence and absence of 1 μM ofDiethylenetriamine/nitric oxide adduct (DETA-NO; Sigma, 17018) for 30min at 25° C. Compounds are subsequently added and incubated for 1 hr at37° C. At the end of the incubation period, the reaction was terminatedand the cells were lysed with the detection reagents from Cisbio Kits.The level of intracellular cGMP was determined using an HTRF-based assaykit (CisBio, 62GM2PEC), which detects the displacement of a fluorescencelabeled cGMP from its specific antibody. The cGMP produced by testcompounds was directly compared to the maximum cGMP production (thisvalue was set to equal 100% activation.) of the published sGC-HDAcompound A:

(Example 1 in WO 2010/065275, published Jun. 10, 2010). The testcompounds' activity were then expressed as a percentage of compound A,the standard in every experiment. This percent activation was calculatedeither in the presence or absence of DETA-NO which was then plotted.Inflection points (IP) and maximum fold induction was derived usingAbase analysis software for 4P fit.

Most preferred compounds had an IP of less than or equal to about 1500nM. Data for the compounds of the Examples is provided in Table 22.

TABLE 22 EX. IP (nM) % Activation EX. IP (nM) % Activation  1A 409 120 64B 302 101  2A 1058 111  65B 1101 136  3A 183 126  66B 238 107  4B 294126  67B 384 115  5BA 132 76  68B 568 109  5BB 330 107  69B 289 139  6A1263 85  70B 649 120  7A 1026 98  71B 73 78  8B 1363 129  72A 42 80  9B1371 118  73B 85 87  10B 456 117  74A 62 94  11B 537 99  75A 238 155 12B 2877 81  76B 99 101  13B 152 86  77B 489 105  14B 525 90  78A 174193  15B 1315 95  79B 843 124  16B 1473 96  80A 733 98  17AB 3781 77  81B504 110  18B 2497 95  82B 1367 107  19B 1042 89  83B 1421 80  20B 220988  84A 130 113  21B 362 93  85A 700 130  22A 423 91  86A 247 102  23B203 109  87B 547 97  24A 210 106  88B 1247 88  25B 201 147  89B 442 108 26B 1922 102  90B 129 112  27B 331 120  91B 132 123  28B 2173 105  92B219 111  29B 686 82  93A 575 63  30B 176 93  94B 178 108  31B 8333 130 95B 157 118  32B 445 79  96B 311 54  33B 804 100  97B 1146 122  34AA437 81  98A 254 83  34AB 771 115  99B 186 110  35B 2794 102 100B 1803109  36B 916 105 101B 2338 111  37B 762 96 102B 573 100  38B 220 98 103B2946 104  39B 1091 82 104B 1372 106  40B 2561 94 105B 2159 97  41B 77985 106B 1499 70  42B 1052 84 107B 397 113  43B 142 105 108B 842 122  44B245 127 109B 1663 78  45B 210 95 110B 1127 78  46B 647 95 111B 9254 86 47B 218 88 112B 2516 130  48A 257 102 113B 568 89  49A 119 91 114A 1340108  50A 407 98 115A 122 79  51B 485 116 116A 608 78  52B 504 109 117A302 69  53A 124 102 118A 3510 86  54A 490 106 119B 839 103  55A 432 105120B 1933 127  56A 134 116 121B 238 118  57B 1083 104 122B 895 115  58B1130 65 123AA 880 79.0  59B 858 116 123AB 1957 95.8  60B 167 128 124AA1600 76.5  61A 299 109 125AB 56 138.4  62A 141 148 126AA 74 89.0  63A104 72 126AB 199 109.2 127A 52 117.1 194A 73 128.3 128A 137 116.8 195A194 103.1 129A 51 98.5 196A 54 90.3 130A 1228 115.7 197B 125 106.2 131B1061 119.9 198B 1071 134.2 132AA 125 108.6 199A 66 108.5 132AB 89 109.2200A 220 120.4 133AA 657 103.8 201A 39 91.2 133AB 714 111.4 202A 212122.5 134AA 807 103.5 203A 330 122.2 135A 254 92.9 204A 47 97.8 136AA 1178.2 206B 549 113.4 136AB 23 71.4 207B 1761 100.1 137AA 121 92.1 208A453 101.4 137AB 38 98.4 209B 2475 94.4 138B 375 114.5 210B 2019 103.0139B 3455 134.8 211A 1176 96.2 140A 798 99.0 212A 119 134.9 141A 19398.7 213A 839 94.9 142B 264 108.8 214A 320 116.1 143B 3379 76.1 215A3701 118.8 144A 1219 93.1 216A 678 132.2 145A 391 82.9 217A 1424 123.6146A 94 82.1 218A 301 102.8 147A 61 73.4 220B 82 112.8 148A 238 87.8221B 150 92.1 149A 111 103.3 222A 71 104.7 150A 294 102.2 223A 210 118.8151A 194 130.6 224A 14 111.3 152A 120 118.1 225B 460 139.8 153A 145118.9 226A 355 112.5 154A 577 103.9 227B 74 63.5 156A 161 93.5 228A 6495.0 157A 185 143.4 229AA 770 114.6 158A 353 88.8 229AB 179 72.9 159A221 112.7 230AA 821 99.1 160B 111 107.8 231AA 113 148.2 161A 291 120.9231AB 529 127.9 162A 69 76.5 232B 4154 89.1 163B 408 90.8 233A 204 141.1164A 439 127.2 234B 265 135.2 165A 48 110.1 235B 626 86.8 166A 40 86.4236A 478 109.8 167B 93 107.3 237B 5871 93.3 168B 207 141.2 238A 609 99.5169B 159 90.3 239A 350 62.3 170B 655 129.9 240B 749 104.0 171A 1218135.1 241A 403 94.8 172A 1034 92.7 242B 3097 107.3 173A 557 83.4 243A3601 101.1 174A 682 120.9 244A 2726 93.3 175A 96 139.1 246A 7124 95.3176B 1465 117.9 247A 4018 86.9 177B 351 125.7 248B 116 106.1 178A 429123.8 249B 2618 98.5 179A 262 117.8 250B 1704 102.5 180A 228 121.4 252B2460 87.6 181A 278 111.9 253A 3629 96.7 182A 238 92.0 254A 1013 123.3183A 88 111.3 255A 1481 108.4 184A 230 97.7 256B 2048 104.4 185A 426109.5 257A 106 84.7 186A 205 83.3 258B 1732 98.2 187A 244 97.1 259B 560116.2 188A 109 123.7 260A 125 135.6 189A 51 115.6 261C 293 112.9 190A 49119.6 261D 444 103.8 191B 133 113.7 262B 27 82.4 192A 1042 102.8 263AA110 82.1 193B 69 89.2

Binding Assay:

The binding potencies of sGC compounds to the human recombinant sGCenzyme were determined in a Size Exclusion Chromatography (SEC)competition binding assay using [³H] Ex-77B as the radioligand.

[³H] Ex-77B was prepared using a standardized tritium exchangeprocedure. The parent (non-labeled) molecule was first iodinated then aPd-catalyzed iodine to tritium exchange provided the labeled compound.

Method:

The binding buffer was composed of 50 mM triethanolamine, pH 7.4, 3 mMMgCl₂, 0.025% BSA, 2 mM dithiothreitol (DTT), 300 μM DETA/NO and 400 μMGTP. Assays were conducted in 96-well plates in a total volume of 200μL. Recombinant human sGC protein (40 ng) was incubated with 1.6 nM [³H]Ex-77B for 24 hours at 37° C. in the presence and absence of variousconcentrations of sGC testing compounds delivered as DMSO solutions togive a total of 1% organic solvent content. Non-specific binding wasdefined by competition with 1 μM of Ex-77B. After the incubation period,the binding mixtures were loaded onto the gel-filtration plate(ThermoFischer Cat. No. 89808) pre-equilibrated with binding buffer andspun at 1000×g for 3 min at 4° C. on a Bench top centrifuge. Thecollected eluates in White Frame Clear Well Isoplates (Perkin Elmer Cat#6005040) received 100 μl of UltimaGold scintillation cocktail. Thesealed plates were shaken vigorously and span, and counted after 6 hourswith a Wallac Microbeta TriLux 1450 LSC & Luminescence Counter (PerkinElmer). Data from competition experiments were analyzed to determineK_(i) values using one site—fit K_(i) equation.

Most preferred compounds had an Ki of less than or equal to about 1 nM.Data for the compounds of the Examples is provided in Table 23.

TABLE 23 EXAMPLE Ki (pM) EXAMPLE Ki (pM)  1A 47  61A 66  2A 322  62A 22 3A 67  64B 75  4B 391  66B 495  5BA 162  67B 154  5BB 182  68B 3100  6A130  69B 101  7A 154  76B 87  9B 374  77B 232  10B 150  78A 944  11B 304 79B 420  12B 2045  80A 755  13B 112  82B 223  14B 210  83B 1737  15B455  84A 166  16B 1135  85A 1497  17AB 936  86A 323  18B 920  87B 785 19B 286  88B 848  20B 4491  89B 343  21B 64  90B 63  22A 78  91B 180 23B 99  92B 175  25B 262  93A 602  26B 266  95B 60  27B 221  96B 12150 28B 536  97B 799  29B 564  98A 395  30B 560 100B 39  31B 1412 101B 26 32B 1700 103B 45  33B 594 105B 42  34AA 138 106B 58  34AB 231 108B 56 35B 1119 109B 1998  36B 908 110B 361  37B 484 111B 1113  38B 145 112B66  39B 3652 113B 64  40B 4379 114A 92  41B 717 116A 296  42B 951 118A166  43B 96 119B 292  44B 123 120B 410  45B 182 121B 234  46B 216 122B326  47B 114 123AA 1231  52B 413 123AB 874  57B 96 124AA 506  58B 493124AB 617  59B 293 125AA 783  60B 102 125AB 336 126AA 100 194A 41 126AB77 195A 92 127A 57 196A 468 128A 111 197B 162 129A 117 198B 107 130A 184199A 70 131B 125 200A 52 132AA 105 201A 151 132AB 74 202A 186 133AA 513203A 71 133AB 359 204A 269 134AA 320 206B 798 134AB 461 207B 95 135A 275208A 253 136AA 252 209B 1642 136AB 218 210B 341 137AA 128 211A 258 137AB204 212A 72 138B 58 213A 123 139B 114 214A 267 140A 227 215A 189 141A665 216A 110 142B 183 217A 67 143B 174 218A 57 144A 594 219A 183 145A299 220B 87 146A 62 221B 163 147A 75 222A 112 148A 123 223A 50 149A 167224A 67 150A 96 225B 342 151A 124 226A 176 152A 31 227B 146 153A 118228A 79 154A 91 229AA 496 155B 420 229AB 238 156A 170 230AA 185 157A 258230AB 280 158A 864 231AA 92 159A 125 231AB 87 160B 62 232B 85 161A 81233A 83 162A 150 234B 947 163B 1852 235B 404 164A 99 236A 158 165A 81237B 193 166A 144 238A 95 167B 70 239A 68 168B 164 240B 75 169B 104 241A121 170B 118 242B 1111 171A 94 243A 62 172A 98 244A 63 173A 252 245B 333174A 173 246A 220 175A 151 247A 242 176B 130 248B 48 177B 118 249B 68178A 116 250B 108 179A 144 251B 182 180A 31 252B 292 181A 94 253A 146182A 124 254A 199 183A 76 255A 73 184A 92 256B 74 185A 165 257A 105 186A120 258B 80 187A 29 259B 111 188A 100 260A 58 189A 49 261C 74 190A 31261D 187 191B 109 262B 97 192A 116 263AA 235 193B 52 263BA 127

Acute Efficacy in Spontaneously Hypertensive Rats (SHR)

Spontaneously hypertensive rats (SHR, male, Charles River) wereimplanted with DSI TA11PA-C40 telemetry device (Data Sciences, Inc., St.Paul, Minn.) under isoflurane or ketamine/metomidine anesthesia. Thetelemetry unit catheter was inserted into the descending aorta via thefemoral artery and the telemetry device was implanted subcutaneously inthe left flank area. Animals were allowed to recover from surgery for 14days before the start of any studies. Blood pressure, heart rate, andactivity signals from conscious, freely moving rats were recordedcontinuously for 30 seconds every 10 minutes. On the day prior toadministration of compound, a single oral dose of vehicle (10%transcutol/20% Cremophor/70% water) was administered to all animals toestablish baseline control data. The blood pressure lowering efficacy ofcompound (PO) or vehicle was evaluated following a single oral gavage.Data were collected as hourly averages, and changes in blood pressurewere calculated by subtracting control baseline data on an hourly basis.Animals were maintained on normal diet with a 12 hour light-dark cycle.

Maximum peak decreases of systolic blood pressure (SBP) in SHR at aparticular P.O. dose (mpk milligrams per kilogram) for the followingExample compounds are provided.

Category A=decrease in SBP in SHRs 5-25 mmHg;Category B=decrease in SBP in SHRs 25-40 mmHg;Category C=decrease in SBP in SHRs >40 mmHg.

TABLE 24 EXAMPLE Dose (P.O. mpk) Category  2A 3 A  5BA 3 B  7A 3 A  9B 3A  10B 3 A  13B 3 A  14B 3 A  21B 3 A  22A 3 A  27B 1 A  33B 3 B  34AA 3A  34AB 1 A  38B 3 A  44B 3 C  45B 3 B  46B 3 A  52B 3 A  58B 3 A  59B 3A  70B 3 A  76B 3 B  77B 1 C  79B 3 A  82B 3 A  84A 1 C  86A 1 A  89B 3B  90B 1 B  92B 0.3 A 121B 3 A

Acute Efficacy in Hypoxia-Induced Pulmonary Hypertension in RatFollowing Intratracheal Administration

Charles River Sprague-Dawley (CD) male rats weighing approximately 350 gwere implanted with HD-S21 dual pressure telemetry transmitters (DataSciences International (DSI)) into the pulmonary artery and femoralartery. This transmitter enables simultaneous measurement of bothpulmonary and systemic hemodynamic parameters in the same animal. Aftera 7-10 day post-operative recovery period, animals were subjected to anormobaric hypoxic (10% oxygen) environment using a Higher Peak MountainAir Generator (MAG-10) connected to a modified rodent cage via a fittedinlet port. Oxygen (at 10%), temperature, humidity, and CO₂ werecontrolled within normal range and animals were maintained on a 12 hourlight-dark cycle with ad libitum access to food and water. After twoweeks exposure to 10% O₂ hypoxic environment, systolic pulmonaryarterial pressure readings increased from ˜25 mmHg to greater than 50mmHg. Using a 48 hour baseline average, animals with readings between50-110 mmHg (standard deviation of less than 10 mmHg) and minimalchanges in systolic systemic blood pressure were enrolled for study.Animals were utilized for up to 2 studies per week for 4 weeks with aminimum of 2 days washout between doses of test agent.

Compound or vehicle was administered intra-tracheally under lightisoflurane anesthesia (5% in oxygen; flow rate 2.0 L/min for 3 minutes).Once anesthetized, rats were placed on an angled intubation stand insupine position and the trachea visualized using a small laryngoscope.Animals then received either 0.5 mL/kg of vehicle or 0.5 mL/kg vehiclecontaining compound intra-tracheally delivered via microsprayer by useof a Penn-Century Microsprayer® needle 3″ (Model IA-1B-GP) attached to a1 mL high pressure syringe (Penn Century-Model B—SYR-PL1000)(Penn-Century, Philadelphia, Pa.). The Microsprayer® tip was insertedinto the trachea up to the point at which the bend in the needle isclose to the tip of the snout, which positions the tip of theMicrosprayer® in front of the carina (bifurcation of trachea at thebronchi). After dose delivery the animal is placed on its back in thehome cage for recovery.

Hemodynamic measurements were continuously recorded and readingsconsolidated to hourly moving averages. Each animal received a vehicleon Day 1 followed by vehicle or test agent on Day 2. Change from vehiclebaseline was calculated by subtracting the hourly Day 1 vehicle responsefrom the hourly Day 2 response and treatment group data was expressed asmean±SEM.

Decreases of systolic blood pressure (SBP) and systolic pulmonaryarterial pressure (PAP) were measured at a particular IT dose (mpkmilligrams per kilogram) for the following Example compounds. Compoundsin the Table 25 achieved a minimum decrease in PAP of ≥15 mmHg for thecorresponding decrease in SBP listed.

Category A=decrease in SBP 0-5 mmHg;Category B=decrease in SBP 5-10 mmHg;Category C=decrease in SBP >10 mmHg.

TABLE 25 EXAMPLE Dose (IT mpk) Category  2A 0.03 mpk A  3A 0.01 mpk A 7A  0.1 mpk B  10B 0.01 mpk A  11B 0.03 mpk B  12B  0.1 mpk B  21B 0.03mpk A  46B 0.03 mpk A  47B 0.03 mpk A  51B 0.01 mpk A  63A 0.01 mpk A 77B 0.03 mpk A  80BA  0.1 mpk B  81B 0.03 mpk B  84A 0.03 mpk A  92B0.03 mpk A  95B 0.03 mpk A 112B 0.01 mpk A 119B 0.03 mpk A 127A 0.03 mpkA 160B 0.01 mpk B 163B 0.03 mpk C 185A 0.01 mpk A 195A 0.01 mpk B 202A0.01 mpk A 220B 0.01 mpk B 222A 0.01 mpk B 235B 0.01 mpk A 239A 0.01 mpkA

1-20. (canceled)
 21. A method for treating a condition selected fromcardiovascular disease, endothelial dysfunction, diastolic dysfunction,atherosclerosis, hypertension, heart failure, pulmonary hypertension(WHO groups I, II, III, IV), angina pectoris, thrombosis, restenosis,myocardial infarction, stroke, cardiac insufficiency, fibrosis,pulmonary hypertonia, erectile dysfunction, asthma, acute respiratorydistress syndrome (ARDS), chronic kidney disease, cystic fibrosis,sickle cell anemia, scleroderma, Raynaud's Syndrome, diabetes, diabeticretinopathy, cirrhosis of the liver, chronic obstructive pulmonarydisease (COPD), acute lung injury, pulmonary fibrosis, or interstitiallung disease, comprising administering a therapeutically effectiveamount of a compound of the Formula (I)

wherein: X is C(H) or N; each R¹ is independently halo, hydroxy, C₁-C₃alkyl, C₃-C₆ cycloalkyl or —O—C₁-C₃ alkyl; R² is: (a.) C₁-C₆ alkyl,wherein said C₁-C₆ alkyl of R² is unsubstituted or substituted by 1 to 6moieties independently selected from fluoro or —O—C₁-C₃ alkyl; (b.) ringC², wherein ring C² is: (i.) C₃-C₁₂ cycloalkyl; (ii.) phenyl; (iii.) a5- or 6-membered monocyclic heteroaryl containing 1 to 2 heteroatomsselected from N, O, or S; or (iv.) a 5- or 6-membered monocyclicheterocyclyl containing 1 to 2 heteroatoms selected from N, O, or S:wherein ring C² is unsubstituted or substituted by 1 to 3 moietiesindependently selected from halo, cyano, C₁-C₃ alkyl, —O—C₁-C₃ alkyl, oroxo; R⁴ is C₁-C₆ alkyl, CF₃, or C₃-C₆ cycloalkyl; ring C³ is: (a.)phenyl; (b.) a 5- or 6-membered monocyclic heteroaryl or a 9- to10-membered bicyclic heteroaryl containing 1 to 3 heteroatoms selectedfrom N, O, or S; (c.) a 5- or 6-membered monocyclic heterocyclylcontaining 1 to 3 heteroatoms selected from N, O, or S; or (d.) C₃-C₆cycloalkyl; each R^(a) is independently selected from halo, cyano, C₁-C₃alkyl, —O—C₁-C₃ alkyl, oxo, or hydroxy; Y is: (a.) a bond; (b.) a groupof the formula

wherein R^(Y1) and R^(Y2) are independently H, C₁-C₃ alkyl, hydroxy,fluoro, C₁-C₃ hydroxyalkyl, or amino; or alternatively R^(Y1) andR^(Y2), together with the carbon atom to which they are attached form aC₃-C₆ cycloalkyl; R^(Y3) and R^(Y4) are independently H, C₁-C₃ alkyl,hydroxy, fluoro, or C₁-C₃ hydroxyalkyl; or alternatively R^(Y3) andR^(Y4), together with the carbon atom to which they are attached form aC₃-C₆ cycloalkyl; (c.) a group of the formula

(d.) ring A^(H), wherein ring A^(H) is C₃-C₆ cycloalkyl or phenyl,wherein ring A^(H) is unsubstituted or substituted by 1 to 3 moietiesindependently selected from halo or C₁-C₃ alkyl; (e.) a group —CH═CH—;or (f.) a group

Z is: (a.) —CO₂H; (b.) —C(O)N(H)OH; (c.)

 (f.) —SO₃H; (g.) —P(═O)(OH)₂; or (h.) —C(O)N(H)S(O)₂CH₃; the subscriptm is 0, 1, or 2; the subscript p is 0, 1, 2, or 3; the subscript q is 0or 1; the subscript r1 is 0, 1, 2, 3, or 4; and the subscript r2 is 0 or1, or a pharmaceutically acceptable salt thereof, to a patient in needthereof. 22-25. (canceled)
 26. The method of claim 21, wherein thecondition is pulmonary hypertension (WHO groups I, II, III, IV).